Submissions for variant NM_000179.3(MSH6):c.1858G>A (p.Gly620Ser)

gnomAD frequency: 0.00001  dbSNP: rs876661043

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000215890	SCV000279329	uncertain significance	not provided	2024-05-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with pancreatic cancer, Lynch syndrome-associated cancers, and/or polyps (PMID: 25980754, 28726808); This variant is associated with the following publications: (PMID: 25980754, 28726808, 21120944, 17531815)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000225881	SCV000283733	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569553	SCV000662369	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	The p.G620S variant (also known as c.1858G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 1858. The glycine at codon 620 is replaced by serine, 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 alteration was also identified in cohort of 302 patients diagnosed with pancreatic ductal adenocarcinoma and a family history positive for pancreatic cancer (Chaffee KG et al. Genet Med. 2018 01;20:119-127). This amino acid position is not well 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.
Counsyl	RCV000662360	SCV000784745	uncertain significance	Lynch syndrome 5	2018-02-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569553	SCV000911026	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 620 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 performed for this variant. This variant has been reported in at least one individual affected with pancreatic cancer, and in an individual affected with Lynch syndrome-associated cancer in the literature (PMID 25980754, 28726808). This variant has been identified in 2/250666 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	RCV000569553	SCV002535668	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-19	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662360	SCV004018444	benign	Lynch syndrome 5	2023-03-27	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. 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].
All of Us Research Program, National Institutes of Health	RCV003998620	SCV004835456	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 620 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least one individual affected with pancreatic cancer, and in an individual affected with Lynch syndrome-associated cancer in the literature (PMID 25980754, 28726808). This variant has been identified in 2/250666 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.
Baylor Genetics	RCV004567677	SCV005055007	uncertain significance	Endometrial carcinoma	2023-12-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541361	SCV004782136	uncertain significance	MSH6-related disorder	2024-02-05	no assertion criteria provided	clinical testing	The MSH6 c.1858G>A variant is predicted to result in the amino acid substitution p.Gly620Ser. This variant has been reported in individuals with pancreatic cancer, Lynch syndrome-associated cancers and/or polyps (Yurgelun et al. 2015. PubMed ID: 25980754. Table S2; Chaffee et al. 2018. PubMed ID: 28726808. Table S2). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/234483/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.