Submissions for variant NM_000179.3(MSH6):c.3101G>A (p.Arg1034Gln)

dbSNP: rs181727939

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000199786	SCV000254302	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000215044	SCV000275662	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-29	criteria provided, single submitter	clinical testing	The p.R1034Q variant (also known as c.3101G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 3101. The arginine at codon 1034 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly 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	RCV000215044	SCV000685351	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1034 of the MSH6 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 been identified in 5/247886 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	RCV001194335	SCV001363796	uncertain significance	not specified	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3101G>A (p.Arg1034Gln) results in a conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 247886 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant was observed in a patient with breast cancer (Tung_2015), however this report does not provide any 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000215044	SCV002535791	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491941	SCV004239312	uncertain significance	Breast and/or ovarian cancer	2023-02-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996999	SCV004837124	uncertain significance	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1034 of the MSH6 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 been identified in 5/247886 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.