Submissions for variant NM_000179.3(MSH6):c.972A>C (p.Lys324Asn)

gnomAD frequency: 0.00004  dbSNP: rs876658610

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216324	SCV000274094	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	The p.K324N variant (also known as c.972A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 972. The lysine at codon 324 is replaced by asparagine, an amino acid with similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This amino acid position is 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.
Invitae	RCV000229706	SCV000283863	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000483787	SCV000566493	uncertain significance	not provided	2023-10-03	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; Observed in an individual with a history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 25980754, 21437237)
Counsyl	RCV000663012	SCV000786027	uncertain significance	Lynch syndrome 5	2018-02-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216324	SCV000904762	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 324 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 with a history of Lynch syndrome associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 1/251398 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	RCV001328357	SCV001519447	uncertain significance	not specified	2021-03-12	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.972A>C (p.Lys324Asn) 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 251398 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.972A>C has been reported in the literature as a VUS in at-least one individual undergoing a hereditary multigene cancer panel testing for Lynch syndrome (example, Yurgelun_2015). This report does 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. 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. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000216324	SCV002536374	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-06	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000663012	SCV004018438	benign	Lynch syndrome 5	2023-03-27	criteria provided, single submitter	clinical testing	This variant is considered 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]. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Baylor Genetics	RCV003462441	SCV004197557	uncertain significance	Endometrial carcinoma	2023-10-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483787	SCV004222067	uncertain significance	not provided	2023-07-19	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754 (2015)). The frequency of this variant in the general population, 0.000004 (1/251398 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	RCV003997842	SCV004837503	uncertain significance	Lynch syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 324 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 with a history of Lynch syndrome associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 1/251398 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.