Gene Symbol PMS2
Synonyms HNPCC4 | LYNCH4 | MLH4 | MMRCS4 | PMS-2 | PMS2CL | PMSL2
Gene Description PMS2, PMS1 homolog 2, mismatch repair system component, interacts with MLH1 to form the MutL-alpha complex, which functions in DNA mismatch repair (PMID: 18157157, PMID: 24333356) and is associated with microsatellite instability (MSI) (PMID: 30121009) and genomic stability (PMID: 31747945). Germline PMS2 mutations are associated with Lynch syndrome (PMID: 15528792), mutations in PMS2 are associated with susceptibility to colon cancer and endometrial cancer (PMID: 24978665), and overexpression has been reported in prostate cancer (PMID: 27803051).
ACMG Incidental List v3.0:
Yes, Lynch syndrome (PMID: 34012068)
5395 7 7p22.1 NM_000535 Tumor suppressor (PMID: 30606230)
Clinical Trials 103
Protein Effect
Variant Description
Associated with drug Resistance
A423T missense unknown PMS2 A423T does not lie within any known functional domains of the Pms2 protein (UniProt.org). A423T demonstrates reduced mismatch repair (MMR) activity compared to wild-type Pms2, but higher MMR activity compared to a Pms2 deficient control in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
C843Y missense loss of function - predicted PMS2 C843Y does not lie within any known functional domains of the Pms2 protein (UniProt.org). C843Y results in reduced mismatch repair (MMR) activity in an in vitro assay compared to wild-type Pms2 and MMR activity similar to a Pms2 deficient control (PMID: 24027009), and therefore, is predicted to lead to a loss of Pms2 protein function.
D414fs frameshift loss of function - predicted PMS2 D414fs results in a change in the amino acid sequence of the Pms2 protein beginning at aa 414 of 862, likely resulting in premature truncation of the functional protein (UniProt.org). D414fs has not been characterized, however, due to the effects of other truncation mutations downstream of D414 (PMID: 12697830), is predicted to lead to a loss of Pms2 protein function.
D60E missense unknown PMS2 D60E does not lie within any known functional domains of the Pms2 protein (UniProt.org). D60E demonstrates reduced mismatch repair compared to wild-type Pms2, but higher MMR activity compared to a Pms2 deficient control in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
D70N missense loss of function - predicted PMS2 D70N does not lie within any known functional domains of the Pms2 protein (UniProt.org). D70N results in reduced mismatch repair (MMR) activity in an in vitro assay (PMID: 23709753), and therefore, is predicted to lead to a loss of Pms2 protein function.
E663A missense unknown PMS2 E663A does not lie within any known functional domains of the Pms2 protein (UniProt.org). E663A demonstrates mismatch repair (MMR) activity comparable to E541K, a polymorphic PMS2 allele, but below the levels of wild-type Pms2 in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
E705K missense loss of function PMS2 E705K does not lie within any known functional domains of the Pms2 protein (UniProt.org). E705K results in reduced mismatch repair (MMR) activity in an in vitro assay (PMID: 16873062, PMID: 24027009).
G132V missense unknown PMS2 G132V does not lie within any known functional domains of the Pms2 protein (UniProt.org). G132V has not been characterized in the scientific literature and therefore, its effect on Pms2 protein function is unknown (PubMed, Dec 2022).
G207E missense unknown PMS2 G207E does not lie within any known functional domains of the Pms2 protein (UniProt.org). G207E results in Pms2 expression level comparable to wild-type protein in cell culture, and demonstrates proficient mismatch repair (MMR) activity and ATPase activity similar to wild-type Pms2 in in vitro assays (PMID: 30653781, PMID: 24027009), but demonstrates higher MMR activity compared to a Pms2 deficient control in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
G480R missense unknown PMS2 G480R does not lie within any known functional domains of the Pms2 protein (UniProt.org). G480R has been identified in sequencing studies (PMID: 31386297), but has not been biochemically characterized and therefore, its effect on Pms2 protein function is unknown (PubMed, Oct 2022).
G750D missense unknown PMS2 G750D does not lie within any known functional domains of the Pms2 protein (UniProt.org). G750D demonstrates reduced mismatch repair compared to wild-type Pms2, but higher MMR activity compared to a Pms2 deficient control in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
G857A missense no effect - predicted PMS2 G857A does not lie within any known functional domains of the Pms2 protein (UniProt.org). G857A demonstrates mismatch repair activity similar to wild-type Pms2 in an in vitro assay (PMID: 24027009), and therefore, is predicted to have no effect on Pms2 protein function.
H479Q missense unknown PMS2 H479Q does not lie within any known functional domains of the Pms2 protein (UniProt.org). H479Q demonstrates reduced mismatch repair (MMR) activity compared to wild-type Pms2, but higher MMR activity compared to a Pms2 deficient control in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
hypermethylation unknown unknown PMS2 hypermethylation indicates an increased methylation of the PMS2 gene. However, the mechanism causing the hypermethylation is unspecified.
I18V missense no effect - predicted PMS2 I18V does not lie within any known functional domains of the Pms2 protein (UniProt.org). I18V demonstrates mismatch repair activity similar to wild-type Pms2 in an in vitro assay (PMID: 24027009), and therefore, is predicted to have no effect on Pms2 protein function.
inact mut unknown loss of function PMS2 inact mut indicates that this variant results in a loss of function of the Pms2 protein. However, the specific amino acid change has not been identified.
K541E missense unknown PMS2 K541E does not lie within any known functional domains of the Pms2 protein (UniProt.org). K541E is a common Pms2 polymorphism (PMID: 18768816, PMID: 23709753, PMID: 24728327), but has not been biochemically characterized and therefore, its effect on Pms2 protein function is unknown (PubMed, Oct 2022).
K593Sfs*2 frameshift loss of function - predicted PMS2 K593Sfs*2 indicates a shift in the reading frame starting at amino acid 593 and terminating 2 residues downstream causing a premature truncation of the 862 amino acid Pms2 protein (UniProt.org). K593Sfs*2 has not been characterized, however, due to the effects of other truncation mutations downstream of D414 (PMID: 12697830), is predicted to lead to a loss of Pms2 protein function.
K651R missense unknown PMS2 K651R does not lie within any known functional domains of the Pms2 protein (UniProt.org). K651R has been identified in the scientific literature (PMID: 30709382, PMID: 30603682), but has not been biochemically characterized and therefore, its effect on Pms2 protein function is unknown (PubMed, Dec 2022).
L263V missense unknown PMS2 L263V does not lie within any known functional domains of the Pms2 protein (UniProt.org). L263V demonstrates reduced mismatch repair (MMR) activity compared to wild-type Pms2, but higher MMR activity compared to a Pms2 deficient control in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
L42_E44del deletion loss of function PMS2 L42_E44del results in the deletion of three amino acids in the Pms2 protein from amino acid 42 to 44 (UniProt.org). L42_E44del results in decreased Pms2 expression in cell culture, reduced mismatch repair activity and a loss of ATPase activity in in vitro assays (PMID: 30653781).
L571I missense unknown PMS2 L571I does not lie within any known functional domains of the Pms2 protein (UniProt.org). L571I demonstrates mismatch repair (MMR) activity comparable to E541K, a polymorphic PMS2 allele, but below the levels of wild-type Pms2 (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
loss unknown loss of function PMS2 loss indicates loss of the PMS2 gene, mRNA, and protein.
M622I missense unknown PMS2 M622I does not lie within any known functional domains of the Pms2 protein (UniProt.org). M622I demonstrates mismatch repair (MMR) activity comparable to E541K, a polymorphic PMS2 allele, but below the levels of wild-type Pms2 (PMID: 24027009), and demonstrates decreased binding to Mlh1 in culture (PMID: 11793469), and therefore, its effect on Pms2 protein function is unknown.
M797R missense unknown PMS2 M797R does not lie within any known functional domains of the Pms2 protein (UniProt.org). M797R demonstrates reduced mismatch repair compared to wild-type Pms2, but higher MMR activity compared to a Pms2 deficient control in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
mutant unknown unknown PMS2 mutant indicates an unspecified mutation in the PMS2 gene.
N575D missense unknown PMS2 N575D does not lie within any known functional domains of the Pms2 protein (UniProt.org). N575D has not been characterized in the scientific literature and therefore, its effect on Pms2 protein function is unknown (PubMed, Oct 2022).
negative unknown loss of function PMS2 negative indicates a lack of the PMS2 gene, mRNA, and/or protein.
P246fs frameshift loss of function - predicted PMS2 P246fs results in a change in the amino acid sequence of the Pms2 protein beginning at aa 246 of 862, likely resulting in premature truncation of the functional protein (UniProt.org). P246fs has not been characterized, however, due to the effects of other truncation mutations downstream of P246 (PMID: 12697830), is predicted to lead to a loss of Pms2 protein function.
P376S missense unknown PMS2 P376S does not lie within any known functional domains of the Pms2 protein (UniProt.org). P376S has not been characterized in the scientific literature and therefore, its effect on Pms2 protein function is unknown (PubMed, Sep 2022).
P470S missense no effect - predicted PMS2 P470S does not lie within any known functional domains of the Pms2 protein (UniProt.org). P470S results in similar levels of mismatch repair activity to wild-type protein (PMID: 23709753), and therefore, is predicted to have no effect on Pms2 protein function.
positive unknown unknown PMS2 positive indicates the presence of the PMS2 gene, mRNA, and/or protein.
Q205P missense unknown PMS2 Q205P does not lie within any known functional domains of the Pms2 protein (UniProt.org). Q205P demonstrates reduced mismatch repair (MMR) activity compared to wild-type Pms2, but higher MMR activity compared to a Pms2 deficient control in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
R20Q missense loss of function PMS2 R20Q does not lie within any known functional domains of the Pms2 protein (UniProt.org). R20Q results in mismatch repair (MMR) proficiency in an in vitro assay (PMID: 23709753), but leads to both an inability to stabilize p73 in vitro and induce apoptosis in response to DNA damage in cell culture, and promotes tumor formation (PMID: 18768816, PMID: 23981578).
R315* nonsense loss of function - predicted PMS2 R315* results in a premature truncation of the Pms2 protein at amino acid 315 of 862 (UniProt.org). R315* results in decreased Pms2 protein expression in a patient sample (PMID: 31056861), and due to the effects of other truncation mutations downstream of R315 (PMID: 12697830), is predicted to lead to a loss of Pms2 protein function.
R563* nonsense loss of function - predicted PMS2 R563* results in a premature truncation of the Pms2 protein at amino acid 563 of 862 (UniProt.org). R563* has not been characterized, however, due to the effects of other truncation mutations downstream of R563 (PMID: 12697830), is predicted to lead to a loss of Pms2 protein function.
R563L missense no effect - predicted PMS2 R563L does not lie within any known functional domains of the Pms2 protein (UniProt.org). R563L demonstrates mismatch repair activity similar to wild-type Pms2 in an in vitro assay (PMID: 24027009), and therefore, is predicted to have no effect on Pms2 protein function.
R802* nonsense unknown PMS2 R802* results in a premature truncation of the Pms2 protein at amino acid 802 of 862 (UniProt.org). R802* has been identified in the scientific literature (PMID: 28805995, PMID: 16507833), but has not been biochemically characterized and therefore, its effect on Pms2 protein function is unknown (PubMed, Dec 2022).
S455F missense unknown PMS2 S455F does not lie within any known functional domains of the Pms2 protein (UniProt.org). S455F has been identified in sequencing studies (PMID: 23017166), but has not been biochemically characterized and therefore, its effect on Pms2 protein function is unknown (PubMed, Feb 2023).
S46I missense loss of function PMS2 S46I does not lie within any known functional domains of the Pms2 protein (UniProt.org). S46I confers a loss of function to the Pms2 protein as it results in reduced mismatch repair (MMR) activity compared wild-type Pms2 and MMR activity similar to a Pms2 deficient control in in vitro assays (PMID: 23709753, PMID: 24027009).
S46N missense loss of function - predicted PMS2 S46N does not lie within any known functional domains of the Pms2 protein (UniProt.org). S46N results in reduced mismatch repair (MMR) activity compared to wild-type Pms2 and MMR activity similar to a Pms2 deficient control in an in vitro assay (PMID: 24027009), and therefore, is predicted to lead to a loss of Pms2 protein function.
T485K missense unknown PMS2 T485K does not lie within any known functional domains of the Pms2 protein (UniProt.org). T485K demonstrates reduced mismatch repair (MMR) activity compared to wild-type Pms2, but higher MMR activity compared to a Pms2 deficient control in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
T511A missense unknown PMS2 T511A does not lie within any known functional domains of the Pms2 protein (UniProt.org). T511A demonstrates mismatch repair (MMR) activity comparable to E541K, a polymorphic PMS2 allele, but below the levels of wild-type Pms2 (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
T511M missense unknown PMS2 T511M does not lie within any known functional domains of the Pms2 protein (UniProt.org). T511M demonstrates reduced mismatch repair (MMR) activity compared to wild-type Pms2, but higher MMR activity compared to a Pms2 deficient control in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.
T597S missense unknown PMS2 T597S does not lie within any known functional domains of the Pms2 protein (UniProt.org). T597S demonstrates mismatch repair (MMR) activity comparable to E541K, a polymorphic PMS2 allele, but below the levels of wild-type Pms2 (PMID: 24027009) and demonstrates decreased binding to Mlh1 in culture (PMID: 11793469), and therefore, its effect on Pms2 protein function is unknown.
V609* nonsense loss of function - predicted PMS2 V609* results in a premature truncation of the Pms2 protein at amino acid 609 of 862 (UniProt.org). V609* results in impaired nuclear localization (PMID: 12697830), and therefore, is predicted to lead to a loss of Pms2 protein function.
V796I missense unknown PMS2 V796I does not lie within any known functional domains of the Pms2 protein (UniProt.org). V796I has not been characterized in the scientific literature and therefore, its effect on Pms2 protein function is unknown (PubMed, Oct 2022).
Y519C missense unknown PMS2 Y519C does not lie within any known functional domains of the Pms2 protein (UniProt.org). Y519C demonstrates mismatch repair (MMR) activity comparable to E541K, a polymorphic PMS2 allele, but below the levels of wild-type Pms2 in an in vitro assay (PMID: 24027009), and therefore, its effect on Pms2 protein function is unknown.