Submissions for variant NM_000251.3(MSH2):c.482T>C (p.Val161Ala)

dbSNP: rs63750126

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000685129	SCV000812602	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-02-01	criteria provided, single submitter	clinical testing	Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. 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. This variant disrupts the p.Val161 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11726306, 15849733, 17101317, 28785832). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 565544). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 161 of the MSH2 protein (p.Val161Ala).
Institute of Human Genetics, University of Leipzig Medical Center	RCV002286419	SCV002576431	likely pathogenic	Ependymoma	2022-08-23	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM5, PS4_SUP, PM1_SUP, PM2_SUP, PP3
Ambry Genetics	RCV002331318	SCV002634039	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-21	criteria provided, single submitter	clinical testing	The p.V161A variant (also known as c.482T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 482. The valine at codon 161 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV002331318	SCV004356598	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 161 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). A functional study assaying the response of haploid cells expressing this variant in response to 6-thioguianine was inconclusive (PMID: 33357406). This variant has been reported in an individual affected with breast cancer(PMID: 34359559). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003992370	SCV004812153	likely pathogenic	Lynch syndrome 1	2022-08-23	criteria provided, single submitter	clinical testing	Criteria applied: PM5,PS4_SUP,PM1_SUP,PM2_SUP,PP3
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554318	SCV001774810	pathogenic	Breast carcinoma	2021-08-08	no assertion criteria provided	clinical testing	invasive ductal carcinoma Estrogen receptor + Progesterone receptor + HER2 receptor -