Submissions for variant NM_000179.3(MSH6):c.719G>A (p.Arg240Gln)

gnomAD frequency: 0.00003  dbSNP: rs542848931

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216536	SCV000274698	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	The p.R240Q variant (also known as c.719G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 719. The arginine at codon 240 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported as a variant of uncertain significance in one individual from a cohort of 60 unrelated probands diagnosed with colorectal cancer and meeting Lynch syndrome criteria. Of note, this individual was also reported to carry an unspecified pathogenic alteration and had no constitutional mismatch repair deficiency (CMMRD) features, however phase was not provided (Schneider NB et al. Cancer Med, 2018 May;7:2078-2088). This alteration has been detected in a Brazilian cohort of 65 patients meeting Amsterdam or Bethesda criteria (InSiGHT. Fam Cancer. 2015 Jun;14 Suppl 1:1-91). This variant has also been identified in at least 2 probands whose Lynch syndrome-associated tumors demonstrated loss of MSH6 expression by immunohistochemistry (Ambry internal data). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476259	SCV000551299	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000481509	SCV000570697	uncertain significance	not provided	2023-09-11	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; This variant is associated with the following publications: (PMID: 25986922, 21437237, 28932927, 29575718, 29684080)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659888	SCV000781783	uncertain significance	Lynch syndrome 5	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216536	SCV000908356	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 240 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 been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 28932927, 29575718) and skin melanoma (PMID: 29684080). This variant has been identified in 5/282444 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	RCV000781606	SCV000919778	uncertain significance	not specified	2020-09-14	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.719G>A (p.Arg240Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251046 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.719G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Soares_2017, Schneider_2018). These reports do not provide unequivocal 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. Five 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.
Baylor Genetics	RCV000659888	SCV001482705	uncertain significance	Lynch syndrome 5	2019-10-11	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Baylor Genetics	RCV003462452	SCV004195766	uncertain significance	Endometrial carcinoma	2024-01-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481509	SCV004222053	uncertain significance	not provided	2023-06-16	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with Lynch syndrome (PMID: 28932927 (2018)), colorectal cancer (PMID: 29575718 (2018)), and skin cutaneous melanoma (PMID: 29684080 (2018)). In a breast cancer association study, the variant was reported in healthy individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/MSH6)). The frequency of this variant in the general population, 0.000023 (3/128894 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997874	SCV004836875	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 240 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 been reported in individuals affected with Lynch syndrome-associated cancer (PMID: 28932927, 29575718) and skin melanoma (PMID: 29684080). This variant has been identified in 5/282444 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.