Submissions for variant NM_000251.3(MSH2):c.2029A>G (p.Thr677Ala)

dbSNP: rs1553369013

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000579590	SCV000685001	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 677 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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	RCV000579590	SCV001174808	likely benign	Hereditary cancer-predisposing syndrome	2022-10-18	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001240812	SCV001413787	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 677 of the MSH2 protein (p.Thr677Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 489929). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV004001257	SCV004825194	uncertain significance	Lynch syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 677 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
GeneDx	RCV004719890	SCV005325756	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a neutral effect: demonstrates sensitivity to 6-TG and mismatch repair (MMR) function similar to wild-type (PMID: 33357406); Identified in a patient with breast and endometrial cancer and with family history of breast cancer who also carried a pathogenic variant in BRCA2 (PMID: 34637943); This variant is associated with the following publications: (PMID: 18822302, 21120944, 33357406, 34637943)
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001574074	SCV001797299	uncertain significance	Breast carcinoma	2021-08-20	no assertion criteria provided	clinical testing	Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive