Submissions for variant NM_000179.3(MSH6):c.1061G>T (p.Gly354Val)

gnomAD frequency: 0.00001  dbSNP: rs730881788

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212644	SCV000211272	uncertain significance	not provided	2023-07-20	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 breast or other cancers (Maxwell et al., 2015; Zhang et al., 2015; Young et al., 2018); This variant is associated with the following publications: (PMID: 25503501, 26580448, 29945567)
Ambry Genetics	RCV000160663	SCV000215588	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	The p.G354V variant (also known as c.1061G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 1061. The glycine at codon 354 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in one individual with early-onset breast cancer and in a pediatric patient diagnosed with acute lymphocytic leukemia (Maxwell KN et al. Genet. Med. 2015 Aug;17(8):630-8; Zhang J et al. N. Engl. J. Med. 2015 Dec;373(24):2336-2346). This alteration has also been reported in one individual with pancreatic cancer (Young E et al. BMC Cancer 2018 Jun;18(1):697). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000198861	SCV000254270	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000662570	SCV000785177	uncertain significance	Lynch syndrome 5	2017-05-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212644	SCV000885720	uncertain significance	not provided	2018-05-21	criteria provided, single submitter	clinical testing	The MSH6 c.1061G>T; p.Gly354Val variant (rs730881788), is reported in the literature in at least one individual with early-onset breast cancer (Maxwell 2015). This variant is reported as uncertain in ClinVar (Variation ID: 182618), and found in the general population with a low overall allele frequency of 0.003% (1/30980 alleles) in the Genome Aggregation Database. The glycine at codon 354 is not highly conserved, and computational programs that predict the effect of missense variants on the protein (SIFT, PolyPhen-2) suggest that this variant is tolerated. However, splicing algorithms (Alamut v.2.11) suggest this variant may have an impact on splicing by creating a cryptic donor site. Due to limited information, the clinical significance of the p.Gly354Val variant is uncertain at this time. REFERENCES Maxwell KN et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. 2015 Aug;17(8):630-8.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212644	SCV000889451	uncertain significance	not provided	2023-03-14	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251202 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with early-onset breast cancer (PMID: 25503501(2015)), pancreatic cancer (PMID: 29945567(2018)) and pediatric acute lymphoblastic leukemia (PMID: 26580448 (2015)). In a large-scale breast cancer association study, the variant was observed in breast cancer cases and in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000160663	SCV000911840	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 354 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 performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25503501) and an individual affected with childhood acute lymphoblastic leukemia (PMID: 26580448). This variant has been identified in 1/251202 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798553	SCV002042029	uncertain significance	Breast and/or ovarian cancer	2021-03-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271427	SCV002556044	uncertain significance	not specified	2024-01-08	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1061G>T (p.Gly354Val) results in a non-conservative amino acid change in 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 3.1e-05 in 1614086 control chromosomes (gnomAD v.4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (3.1e-05 vs 0.00014), allowing no conclusion about variant significance. c.1061G>T has been reported in the literature in at least one individual affected with early onset breast cancer (Maxwell_2015) and in individuals with other cancers without strong evidence for causality (e.g. Zhang_2015, Young_2018). These reports do not provide unequivocal conclusions about association of the variant with disease. 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: 25503501, 26580448, 29945567). ClinVar contains an entry for this variant (Variation ID: 182618). Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000662570	SCV003928136	uncertain significance	Lynch syndrome 5	2023-04-27	criteria provided, single submitter	clinical testing	The MSH6 c.1061G>T (p.Gly354Val) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have not been performed. This variant has been reported in an individual with pancreatic cancer (PMID: 29945567). This variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc.	RCV000662570	SCV004019001	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
All of Us Research Program, National Institutes of Health	RCV003998491	SCV004837592	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 354 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). 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 been reported in an individual affected with breast cancer (PMID: 25503501) and an individual affected with childhood acute lymphoblastic leukemia (PMID: 26580448). This variant has been identified in 1/251202 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.