Submissions for variant NM_000251.3(MSH2):c.687del (p.Ala230fs)

dbSNP: rs63749897

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076681	SCV000107716	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Invitae	RCV000524417	SCV000548211	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-02-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91177). This variant is also known as a 1bp deletion at codons 227-229. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 10404063, 10480359, 15849733, 15926618). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala230Leufs*16) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).
GeneDx	RCV000202204	SCV000568622	pathogenic	not provided	2019-11-14	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 23741719, 15926618, 10480359, 15849733, 10404063, 26648449, 27300758, 24933100, 16206289, 30521064, 31118792, 32885271)
Ambry Genetics	RCV001025755	SCV001188005	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-27	criteria provided, single submitter	clinical testing	The c.687delA pathogenic mutation, located in coding exon 4 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 687, causing a translational frameshift with a predicted alternate stop codon (p.A230Lfs*16). This mutation has been reported in the germline of multiple individuals with HNPCC/Lynch syndrome from various ethnic backgrounds; several of which had tumors that demonstrated high microsatellite instability and/or loss of MSH2 and MSH6 staining on immunohistochemistry (IHC) and had family history meeting Amsterdam criteria (Wang Q et al. Hum. Genet.;105:79-85; Bai YQ et al. Int. J. Cancer, 1999 Aug;82:512-5; Wolf B et al. Wien Klin Wochenschr, 2005 Apr;117:269-77; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Stojcev Z et al. Acta Biochim Pol, 2013 Jun;60:195-8; Batte BA et al. Gynecol Oncol, 2014 Aug;134:319-25; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). This mutation has also been reported in a patient with breast cancer (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). Of note, this alteration is also designated as "228-229 Del A" and "1 bp deletion codons 227-229" in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175575	SCV001339208	pathogenic	Hereditary nonpolyposis colon cancer	2020-03-27	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.687delA (p.Ala230LeufsX16) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251224 control chromosomes. c.687delA has been reported in the literature in multiple individuals affected with Hereditary Non-Polyposis Colon Cancer (eg. Jiang_2019, Mangold_2005, Wang_1999, Wolf_2005, Bai_1999). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003452959	SCV004187922	pathogenic	Lynch syndrome 1	2023-07-27	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV003452959	SCV004196916	pathogenic	Lynch syndrome 1	2022-02-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202204	SCV000257194	pathogenic	not provided		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353660	SCV000592476	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2, p.Ala230LeufsX16 variant was identified in 2 of 3660 proband chromosomes (frequency: 0.001) from individuals or families of Austrian and German ethnicity with Lynch Syndrome, and was not identified in 100 control chromosomes from healthy individuals (Mangold 2005, Wolf 2005). The variant was also identified in dbSNP (ID: rs63749897) as “With Pathogenic allele”. The variant was further identified in the ClinVar and Clinvitae databases, listed by InSIGHT and the Mayo Clinic Genetic Testing Laboratories as pathogenic; in the COSMIC database, 1x with a histology of Adenocarcinoma with a confirmed somatic mutation; in the InSiGHT Colon Cancer Gene Variant database (LOVD), 11x as Class 5; and in the UMD database 2x with a causal classification. The variant was also identified by our laboratory in 1 individual with endometrial cancer. This variant was not identified in the 1000 Genomes Project, in the NHLBI GO Exome Sequencing Project, and in the Exome Aggregation Consortium (Mar 14, 2016) databases nor was it identified in the MutDB, Zhejiang Colon Cancer (LOVD), MMR Gene Unclassified Variants, and Mismatch Repair Genes Variant Databases. The c.687delA variant is predicted to cause a frameshift, which alters the amino acid sequence beginning at codon 230 and leads to a premature stop codon 16 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.