Submissions for variant NM_000179.3(MSH6):c.3724_3726del (p.Arg1242del)

dbSNP: rs63749942

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074918	SCV000108130	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability 0.95-0.99
Ambry Genetics	RCV000129144	SCV000183865	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	clinical testing	The c.3724_3726delCGT pathogenic mutation (also known as p.R1242del) is located in coding exon 8 of the MSH6 gene. This variant results from an in-frame CGT deletion at nucleotide positions 3724 to 3726. This results in the in-frame deletion of an arginine at codon 1242. This alteration was identified in an individual diagnosed with an MSH6-deficient rectal cancer at age 42 and a family history meeting the Amsterdam II criteria; this same alteration was present in this individual's brother, who was diagnosed with rectal cancer at age 53, and mother, who was diagnosed with endometrial cancer at age 54 and ascending colon cancer at age 78 (Roncari B et al. Clin. Genet. 2007 Sep;72:230-7). This alteration has also been reported in multiple other patients with a personal and/or family history consistent with Lynch syndrome, including several demonstrating loss of MSH6 protein by immunohistochemistry (IHC) analysis (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201; Batte BA et al. Gynecol. Oncol. 2014 Aug;134(2):319-25; Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-1389; Ambry internal data). In addition, a missense variant impacting codon 1242 (p.R1242H) has been detected in trans with a pathogenic MSH6 mutation in an individual whose clinical presentation was consistent with CMMR-D due to biallelic MSH6 mutations and had isolated absence of MSH6 in both tumor and normal tissue by IHC (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000255857	SCV000322122	likely pathogenic	not provided	2020-02-03	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Observed in individuals with endometrial, skin, and colorectal cancer, segregating with disease in at least one family, and immunohistochemistry (IHC) of one rectal and one endometrial tumor revealed absence of MSH6 protein (Roncari 2007, Batte 2014, Ring 2016, Ponz de Leon 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 17718861, 24933100, 24763289, 20028993, 24362816, 27443514, 29025352)
Invitae	RCV000524185	SCV000551262	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-08	criteria provided, single submitter	clinical testing	This variant, c.3724_3726del, results in the deletion of 1 amino acid(s) of the MSH6 protein (p.Arg1242del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587781362, gnomAD 0.002%). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 17718861, 20028993, 22144684, 24933100, 27443514). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89450). This variant disrupts the p.Arg1242 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23729658, 24763289). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129144	SCV000690391	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This variant causes a deletion of the conserved arginine at codon 1242 located in the ATPase domain of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 20028993; ClinVar SCV000183865.7), colorectal cancer (PMID: 17718861), and endometrial cancer (PMID: 24933100, 27443514). This variant has been shown to segregate with colorectal cancer in three members of a family (PMID: 17718861). Loss of MSH6 protein expression has been observed in tumor tissues from two affected carriers (PMID: 17718861, 24933100). This variant has also been observed in an individual affected with constitutional mismatch repair deficiency who carried a pathogenic MSH6 variant in trans (ClinVar SCV000183865.7). A multifactorial likelihood analysis using genetic data, computational prediction and tumor pathology has indicated that this variant has a high probability of being pathogenic (PMID: 24362816). This variant has been identified in 2/251212 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Missense variants occurring at this codon, p.Arg1242His and p.Arg1242Ser, are thought to be disease-causing (Clinvar variation ID: 140866, 89449), indicating the importance of arginine at this codon for MSH6 protein function. Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532986	SCV001748819	likely pathogenic	Hereditary nonpolyposis colon cancer	2022-11-22	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3724_3726delCGT (p.Arg1242del) results in an in-frame deletion that is predicted to remove one amino acids from the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of encoded protein. The variant allele was found at a frequency of 8e-06 in 251212 control chromosomes (gnomAD). c.3724_3726delCGT has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and endometrial cancer (e.g. Roncari_2007, Batte_2014, Espenschied_2017, Bennett_2021) and was shown to co-segregate with disease in at least one HNPCC family (Roncari_2007). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters including one expert panel (InSiGHT) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243694	SCV002512751	likely pathogenic	Lynch syndrome 5	2021-12-15	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderate, PM4 moderate, PP1 supporting
Myriad Genetics, Inc.	RCV002243694	SCV004185564	likely pathogenic	Lynch syndrome 5	2023-08-25	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20028993, 17718861]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV003460690	SCV004198169	pathogenic	Endometrial carcinoma	2022-02-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255857	SCV004222007	likely pathogenic	not provided	2022-09-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251212 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Lynch syndrome (PMIDs: 28514183 (2017), 27443514 (2016), and 20028993 (2010)), colorectal cancer (PMIDs: 33654310 (2021) and 17718861 (2007)), and endometrial cancer (PMID: 24933100 (2014)). The variant was found to co-segregate with disease within a family with rectum cancer, colon cancer, endometrial cancer, or polyps (PMID: 17718861 (2007)). Based on the available information, this variant is classified as likely pathogenic.
All of Us Research Program, National Institutes of Health	RCV000074918	SCV004835119	pathogenic	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This variant causes a deletion of the conserved arginine at codon 1242 located in the ATPase domain of the MSH6 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome (PMID: 20028993; ClinVar SCV000183865.7), colorectal cancer (PMID: 17718861), and endometrial cancer (PMID: 24933100, 27443514). This variant has been shown to segregate with colorectal cancer in three members of a family (PMID: 17718861). Loss of MSH6 protein expression has been observed in tumor tissues from two affected carriers (PMID: 17718861, 24933100). This variant has also been observed in an individual affected with constitutional mismatch repair deficiency who carried a pathogenic MSH6 variant in trans (ClinVar SCV000183865.7). A multifactorial likelihood analysis using genetic data, computational prediction and tumor pathology has indicated that this variant has a high probability of being pathogenic (PMID: 24362816). This variant has been identified in 2/251212 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Missense variants occurring at this codon, p.Arg1242His and p.Arg1242Ser, are thought to be disease-causing (Clinvar variation ID: 140866, 89449), indicating the importance of arginine at this codon for MSH6 protein function. Based on the available evidence, this variant is classified as Pathogenic.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249986	SCV001424000	pathogenic	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing