Submissions for variant NM_000251.3(MSH2):c.1267A>G (p.Lys423Glu)

gnomAD frequency: 0.00001  dbSNP: rs201059765

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547106	SCV000625244	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774563	SCV000908298	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 423 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000774563	SCV001170861	likely benign	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
All of Us Research Program, National Institutes of Health	RCV004003729	SCV004832712	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 423 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005056137	SCV005726077	uncertain significance	not specified	2024-11-21	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.1267A>G (p.Lys423Glu) results in a conservative amino acid change located in the DNA-binding domain of DNA mismatch repair MUTS family (IPR007696) 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 1.2e-05 in 251226 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1267A>G has been reported in the literature in individuals affected with Breast cancer and Pancreatic cancer, without strong evidence for causality (Hu_2022, Yin_2022), and large case-control studies evaluating breast cancer genetic risk also reported this variant was not significantly enriched in the case cohorts (Dorling_2021, Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 35449176, 36243179, 35171259). ClinVar contains an entry for this variant (Variation ID: 455481). Based on the evidence outlined above, the variant was classified as uncertain significance.