Submissions for variant NM_000535.7(PMS2):c.936G>A (p.Met312Ile)

gnomAD frequency: 0.00041  dbSNP: rs139194813

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132451	SCV000187545	likely benign	Hereditary cancer-predisposing syndrome	2019-05-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000590247	SCV000211578	likely benign	not provided	2021-04-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26580448, 25186627)
Invitae	RCV001085599	SCV000218523	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260258	SCV000697403	likely benign	not specified	2022-12-23	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.936G>A (p.Met312Ile) results in a conservative amino acid change located in the DNA mismatch repair protein, N-terminal domain (IPR002099) and S5 domain 2-like domains (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 282666 control chromosomes (gnomAD), predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although this data should be interpreted with caution for PMS2 variants since there are a large number of pseudogenes, the sequence surrounding this variant appears to have low pseudogene overlap via BLAT. c.936G>A has been reported in the literature in individuals affected with pediatric cancer, breast cancer, and hereditary colorectal cancer without evidence for causality (examples- Zhang_2015, Tung_2014, Marabelli_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: two classify the variant as uncertain significance, six as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000662505	SCV000785032	uncertain significance	Lynch syndrome 4	2017-03-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132451	SCV000902808	likely benign	Hereditary cancer-predisposing syndrome	2016-03-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590247	SCV001134617	likely benign	not provided	2023-04-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000662505	SCV001137311	likely benign	Lynch syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001270440	SCV001450726	likely benign	Lynch syndrome	2020-12-02	criteria provided, single submitter	clinical testing	The PMS2 c.936G>A (p.Met312Ile) missense change has a maximum subpopulation frequency of 0.1% in gnomAD v2.1.1 (BS1; https://gnomad.broadinstitute.org/variant/7-6031656-C-T). This variant results in a conservative amino acid change at a poorly conserved residue, and six of seven in silico tools predict a benign effect of this variant on protein function (BP4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP4.
Sema4, Sema4	RCV000132451	SCV002530407	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662505	SCV004019808	likely benign	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
PreventionGenetics, part of Exact Sciences	RCV003415967	SCV004107934	uncertain significance	PMS2-related condition	2024-02-28	criteria provided, single submitter	clinical testing	The PMS2 c.3G>A variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported in individuals with leukemia, breast, and kidney cancer (Supplement, Tung et al. 2015. PubMed ID: 25186627; Table S4a, referred to as M312I/rs139194813, Zhang et al. 2015. PubMed ID: 26580448; Table S9, TCGA ID: KIRP_5561-10A, Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.10% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142959/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.