Submissions for variant NM_000179.3(MSH6):c.2597A>C (p.Lys866Thr)

gnomAD frequency: 0.00004  dbSNP: rs190075874

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222631	SCV000277588	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-22	criteria provided, single submitter	clinical testing	The p.K866T variant (also known as c.2597A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 2597. The lysine at codon 866 is replaced by threonine, an amino acid with similar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration has been predicted benign by one computational tool (PON-MMR2) assessing the probability of pathogenicity of variants in mismatch repair genes (Niroula A et al. Hum. Mutat. 2015 Dec;36:1128-34). 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	RCV000524146	SCV000551133	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000759136	SCV000568032	uncertain significance	not provided	2023-07-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with cancer undergoing hereditary cancer testing (Li et al., 2020); This variant is associated with the following publications: (PMID: 26333163, 23621914, Abdelraheem[article], 31391288, 17531815, 21120944)
Genetic Services Laboratory, University of Chicago	RCV000479488	SCV000595853	uncertain significance	not specified	2016-10-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000662498	SCV000785020	uncertain significance	Lynch syndrome 5	2017-03-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759136	SCV000888261	uncertain significance	not provided	2017-10-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222631	SCV001343665	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 866 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 a cohort of African men diagnosed with prostate cancer (PMID: 32832836). This variant has been identified in 6/281184 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.
Sema4, Sema4	RCV000222631	SCV002535755	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-04	criteria provided, single submitter	curation
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137607	SCV003806765	uncertain significance	Endometrial carcinoma	2022-06-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated
Myriad Genetics, Inc.	RCV000662498	SCV004019063	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV003137607	SCV004195780	uncertain significance	Endometrial carcinoma	2023-05-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004542741	SCV004777914	uncertain significance	MSH6-related disorder	2024-01-17	criteria provided, single submitter	clinical testing	The MSH6 c.2597A>C variant is predicted to result in the amino acid substitution p.Lys866Thr. This variant has been reported in an individual with an unspecified type of cancer and an individual of African ancestry whose cancer status was not disclosed (Table S5, Li et al. 2020. PubMed ID: 31391288; Table S2, Matejcic et al. 2020. PubMed ID: 32832836). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD. It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89291/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV003997079	SCV004842737	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 866 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 a cohort of African men diagnosed with prostate cancer (PMID: 32832836). This variant has been identified in 6/281184 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.