Submissions for variant NM_000179.3(MSH6):c.3037AAG[1] (p.Lys1014del)

dbSNP: rs267608073

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524151	SCV000261496	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This variant, c.3040_3042del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Lys1014del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs753885956, gnomAD 0.001%). This variant has been observed in individuals with Lynch syndrome (PMID: 12658575, 18301448, 26483394; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 1013delCTT and c.3037_3039delAAG, p.Lys1013del. ClinVar contains an entry for this variant (Variation ID: 89333). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000409973	SCV000489395	uncertain significance	Lynch syndrome 5	2016-09-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000759857	SCV000565230	likely pathogenic	not provided	2022-11-26	criteria provided, single submitter	clinical testing	Observed in individuals with personal or family history of HNPCC-related cancers referred for genetic testing at GeneDx and in published literature, including some with tumor studies consistent with pathogenic variants in this gene (Wagner et al., 2003; Steinke et al., 2008; Turner et al., 2019); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Also known as c.3037_3039delAAG, p.Lys1013del, c.3403del3, and 1013delCTT; This variant is associated with the following publications: (PMID: 12658575, 18301448, 26483394, 29875428, 32002723, 32123317, 21120944, 17531815)
Ambry Genetics	RCV000491707	SCV000580309	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-25	criteria provided, single submitter	clinical testing	The c.3040_3042delAAG variant (also known as p.K1014del) is located in coding exon 4 of the MSH6 gene. This variant results from an in-frame AAG deletion between nucleotide positions 3040 and 3042, resulting in the deletion of the amino acid lysine at codon 1014. This alteration has been identified in several individuals whose hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch associated tumors displayed high microsatellite instability (MSI-H) and/or isolated loss of MSH6 expression by immunohistochemistry (IHC) (Ambry internal data). This alteration has also been reported in individuals and families with HNPCC/Lynch associated cancers including one individual with pancreatic cancer (Hu C, et al. Cancer Epidemiol. Biomarkers Prev. 2015 Oct; Wagner A, et al. Am. J. Hum. Genet. 2003 May; 72(5):1088-100; Turner SA et al. Genet. Med., 2018 Jun). In addition, it was reported in a German individual who met Bethesda criteria and was diagnosed with MSI-H colorectal cancer at age 38 that displayed loss of both MSH2/MSH6 expression by IHC, but no mutations in MSH2 were detected (Steinke V et al. Eur. J. Hum. Genet., 2008 May;16:587-92). Of note, this alteration is also designated as 1013delCTT, c.3037_3039delAAG and p.Lys1013del in published literature. Based on an internal structural assessment, this alteration disrupts the fold of the lever domain (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This amino acid position is highly conserved through mammals, but not in all available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000491707	SCV000690312	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-17	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid in the lever domain in exon 4 of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with or suspected of having Lynch syndrome (PMID: 12658575, 18301448, 32002723; ClinVar SCV000580309.5, SCV000261496.10), as well as pancreatic cancer (PMID: 26483394) and uterine and/or ovarian cancer (PMID: 29875428, 29684080). This variant has been identified in 1/220392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759857	SCV000889479	likely pathogenic	not provided	2023-01-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000045 (1/220392 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with colorectal cancer (PMIDs: 12658575 (2003), 18301448 (2008)), uterine cancer (PMID: 29875428 (2018)), pancreatic cancer (PMID: 26483394 (2015)), an undescribed Lynch syndrome-associated cancer (PMID: 32002723 (2020)), as well as affected internal patients. Based on the available information, this variant is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290595	SCV001478684	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-10-27	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3040_3042delAAG (p.Lys1014del) results in an in-frame deletion that is predicted to remove one amino acids from DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein. The variant allele was found at a frequency of 4.5e-06 in 220392 control chromosomes (gnomAD). c.3040_3042delAAG has been reported in the literature in comprehensively genotyped individuals affected with Lynch syndrome and associated tumors, supported by characteristic IHC and MSI findings (example, Wagner_2003, Steinke_2008, Hu_2016, Turner_2019, Morak_2020). These data indicate that the variant is likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic (n=1), likely pathogenic, n=2, VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV000409973	SCV004019026	likely pathogenic	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. This variant is expected to disrupt protein structure [Myriad internal data].
Baylor Genetics	RCV003466945	SCV004195653	likely pathogenic	Endometrial carcinoma	2023-07-17	criteria provided, single submitter	clinical testing