Submissions for variant NM_000179.3(MSH6):c.2006T>C (p.Ile669Thr)

gnomAD frequency: 0.00001  dbSNP: rs555209664

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130794	SCV000185688	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.I669T variant (also known as c.2006T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 2006. The isoleucine at codon 669 is replaced by threonine, an amino acid with similar properties. This variant has been reported in Brazilian individuals fulfilling either Bethesda or Amsterdam criteria for Lynch syndrome (Soares BL et al. Fam. Cancer 2017 Sep https://doi.org/10.1007/s10689-017-0043-5; Schneider NB et al. Cancer Med, 2018 May;7:2078-2088). This amino acid position is poorly 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	RCV001083193	SCV000254288	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679222	SCV000601525	uncertain significance	not provided	2024-11-06	criteria provided, single submitter	clinical testing	The MSH6 c.2006T>C (p.Ile669Thr) variant has been reported in the published literature in individuals affected with colorectal cancer (PMIDs: 31927803 (2020), 29575718 (2018)), Lynch syndrome (PMID: 28932927 (2018)), breast cancer (PMID: 35534704 (2022)), and other unspecified cancers (PMID: 31391288 (2020)). In a large scale breast cancer association study, this variant has been observed in 1 breast cancer case and 1 reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.00017 (6/34582 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000130794	SCV000685247	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 669 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 individuals affected with or suspected of having Lynch syndrome (PMID: 28932927, 29575718, 31391288, 31927803), or breast cancer (DOI: 10.1101/2021.04.15.21255554). This variant has also been identified in 10/251038 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.
PreventionGenetics, part of Exact Sciences	RCV000679222	SCV000805855	uncertain significance	not provided	2017-03-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000507463	SCV001361704	uncertain significance	not specified	2022-06-23	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2006T>C (p.Ile669Thr) results in a non-conservative amino acid change located in the connector domain (IPR007860) of 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 4e-05 in 251038 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (4e-05 vs 0.00014), allowing no conclusion about variant significance. c.2006T>C has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer. 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000679222	SCV001791272	uncertain significance	not provided	2023-05-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal or other cancers (Soares et al., 2017; Schneider et al., 2018; Greenberg et al., 2020; Li et al., 2020); This variant is associated with the following publications: (PMID: 23621914, 28932927, 26333163, 29575718, 31927803, 17531815, 21120944, 22290698, 31391288)
Sema4, Sema4	RCV000130794	SCV002535690	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-25	criteria provided, single submitter	curation
Baylor Genetics	RCV003460666	SCV004197741	uncertain significance	Endometrial carcinoma	2024-02-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997070	SCV004838259	uncertain significance	Lynch syndrome	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 669 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 individuals affected with or suspected of having Lynch syndrome (PMID: 28932927, 29575718, 31391288, 31927803), or breast cancer (DOI: 10.1101/2021.04.15.21255554). This variant has also been identified in 10/251038 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.