Submissions for variant NM_000179.3(MSH6):c.2511C>G (p.His837Gln)

gnomAD frequency: 0.00002  dbSNP: rs587779925

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212667	SCV000149301	uncertain significance	not provided	2022-07-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Tung et al., 2015); This variant is associated with the following publications: (PMID: 17531815, 25186627, 21120944)
Ambry Genetics	RCV000115392	SCV000184768	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	The p.H837Q variant (also known as c.2511C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2511. The histidine at codon 837 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported as a variant of uncertain significance in a female breast cancer patient from a cohort of 1781 individuals referred for commercial BRCA1/2 gene testing (Tung N et al. Cancer. 2015 Jan;121:25-33). 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.
Invitae	RCV000195931	SCV000254297	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000412127	SCV000488057	uncertain significance	Lynch syndrome 5	2015-12-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115392	SCV000904019	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 837 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 been reported in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 6/248300 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	RCV001193702	SCV001362736	uncertain significance	not specified	2019-11-26	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2511C>G (p.His837Gln) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248300 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2511C>G has been reported in the literature in at least one individual affected with hereditary breast cancer (Tung_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with another pathogenic variant has been reported (MLH1 c.1381A>T, p.K461X; internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212667	SCV001470351	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with breast cancer (PMID: 25186627 (2015)). The frequency of this variant in the general population, 0.000045 (5/112258 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV000412127	SCV004019019	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 trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Baylor Genetics	RCV003460814	SCV004195611	uncertain significance	Endometrial carcinoma	2023-08-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997241	SCV004842526	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 837 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 been reported in an individual affected with breast cancer (PMID: 25186627). This variant has been identified in 6/248300 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354925	SCV001549653	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.His837Gln variant was not identified in the literature nor was it identified in the GeneInsight-COGR, COSMIC, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs587779925) as “With Uncertain significance allele”, and in the ClinVar and Clinvitae databases (4x classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl). The variant was identified in control databases in 6 of 244020 chromosomes at a frequency of 0.000025 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 15214 chromosomes (freq: 0.000066), European Non-Finnish in 5 of 110424 chromosomes (freq: 0.000045), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.His837Gln residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.