Submissions for variant NM_000179.3(MSH6):c.2156C>T (p.Thr719Ile)

gnomAD frequency: 0.00003  dbSNP: rs373418713

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205525	SCV000260631	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214718	SCV000274125	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-10	criteria provided, single submitter	clinical testing	The p.T719I variant (also known as c.2156C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2156. The threonine at codon 719 is replaced by isoleucine, an amino acid with similar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This alteration was also identified in an individual diagnosed with breast cancer (Nikitin AG et al. Front Oncol, 2020 May;10:666). This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health	RCV000214718	SCV000685260	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 719 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 an individual affected with breast cancer (PMID: 32547938). This variant has been identified in 2/282334 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985830	SCV001134405	uncertain significance	not provided	2018-10-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000985830	SCV001814806	uncertain significance	not provided	2021-08-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016) In silico analysis supports that this missense variant does not alter protein structure/function Observed in an individual with breast cancer (Nikitin 2020) This variant is associated with the following publications: (PMID: 23621914, 32547938)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002254688	SCV002526082	uncertain significance	Lynch syndrome 5	2022-05-24	criteria provided, single submitter	clinical testing	The MSH6 c.2156C>T (p.Thr719Ile) missense change has a maximum subpopulation frequency of 0.0016% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). It is predicted to have a benign effect on protein function (BP4), but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with breast cancer (PMID: 32547938). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993891	SCV004813488	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2156C>T (p.Thr719Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250934 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2156C>T has been reported in the literature in an individual affected with breast cancer who underwent targeted sequencing of DNA mismatch repair genes (Nikitin_2020). The variant was also reported in a study where it was absent from a cohort of individuals with colorectal cancer or polyps, but was found in two ethnically-matched controls from the NHLBI GO Exome Sequencing Project dataset (Rosenthal_2018). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. 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: 32547938, 30267214). ClinVar contains an entry for this variant (Variation ID: 220238). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997625	SCV004836063	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 719 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 an individual affected with breast cancer (PMID: 32547938). This variant has been identified in 2/282334 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.