Submissions for variant NM_000251.3(MSH2):c.704_705del (p.Lys235fs)

dbSNP: rs281864944

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076686	SCV000107721	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
GeneDx	RCV000484029	SCV000568623	pathogenic	not provided	2016-08-01	criteria provided, single submitter	clinical testing	This deletion of two nucleotides in MSH2 is denoted c.704_705delAA at the cDNA level and p.Lys235ArgfsX20 (K235RfsX20) at the protein level. The normal sequence, with the bases that are deleted in braces, is ACAA[AA]GACA. The deletion causes a frameshift which changes a Lysine to an Arginine at codon 235, and creates a premature stop codon at position 20 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.704_705delAA has been identified in association with colon cancer (Syngal 1999, Mangold 2005). We consider this variant to be pathogenic.
Ambry Genetics	RCV000491296	SCV000580443	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-17	criteria provided, single submitter	clinical testing	The c.704_705delAA pathogenic mutation, located in coding exon 4 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 704 to 705, causing a translational frameshift with a predicted alternate stop codon (p.K235Rfs*20). This mutation has been identified in one family fulfilling Amsterdam II criteria (Syngal S et al. JAMA. 1999 Jul;282:247-53), as well as in one individual of German descent fulfilling Bethesda criteria (Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702). This mutation was also detected in an individual with a family history of urinary tract cancers (Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199). 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	RCV000076686	SCV000696280	pathogenic	Lynch syndrome	2017-04-20	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.704_705delAA (p.Lys235Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 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 (e.g. c.1030C>T/ p.Gln344X; c.1147C>T/ p.Arg383X; c.1165C>T/ p.Arg389X; c.1189C>T/ p.Gln397X). In addition, the variant of interest has been reported as pathogenic in multiple affected individuals via publications (Mangold_IJC_2005; Syngal_MLH1_JAMA_1999) and in one reputable database. One in silico tool predicts a damaging outcome for this variant. The variant of interest is absent in a large, broad control population, ExAC in 121020 control chromosomes. Taken together, this variant is classified as pathogenic.
Invitae	RCV000688140	SCV000815741	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-03-07	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: 91182). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 10422993, 15849733). This variant is present in population databases (rs281864944, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Lys235Argfs*20) 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).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000076686	SCV000967752	pathogenic	Lynch syndrome	2018-03-09	criteria provided, single submitter	clinical testing	The p.Lys235fs variant in MSH2 has been reported in 3 individuals with Lynch syn drome-associated cancers (Mangold 2005, Syngal 1999) and been identified in 1/11 1640 European chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org; dbSNP rs281864944). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positio n 235 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozy gous loss of function of the MSH2 gene is an established disease mechanism in in dividuals with Lynch syndrome. In addition, this variant was classified as patho genic on Sep 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV00 0107721.2). In summary, this variant meets criteria to be classified as pathogen ic for Lynch syndrome in an autosomal dominant manner based upon presence in mul tiple affected individuals, low frequency in the general population, and the pre dicted impact on the protein. ACMG/AMP Criteria applied (Richards 2015): PVS1; P M2; PS4_Supporting.
Color Diagnostics, LLC DBA Color Health	RCV000491296	SCV001354532	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-29	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 4 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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 two suspected hereditary nonpolyposis colorectal cancer families (PMID: 10422993, 15849733) and a healthy control from a pancreatic case-control study (PMID: 29922827). This variant has been identified in 1/251348 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV003452961	SCV004187985	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.