Submissions for variant NM_000179.3(MSH6):c.944C>G (p.Ser315Cys)

gnomAD frequency: 0.00001  dbSNP: rs63750491

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566795	SCV000662506	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-15	criteria provided, single submitter	clinical testing	The p.S315C variant (also known as c.944C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 944. The serine at codon 315 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586030	SCV000695935	uncertain significance	not provided	2017-03-27	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.944C>G (p.Ser315Cys) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution. The variant does not lie within a known functional domain (InterPro and UniProt) and 3/5 in silico tools predict a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts that this variant does not affect ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant was found in 3/121192 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). To our knowledge, the variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae	RCV000696871	SCV000825451	benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000566795	SCV001344144	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-03	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 315 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/251292 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.
GeneDx	RCV000586030	SCV001767240	uncertain significance	not provided	2023-02-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 29121415, 29684080)
All of Us Research Program, National Institutes of Health	RCV004000879	SCV004834934	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 315 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/251292 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.