rs63749811

Positions:

• chr2-47476473-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.2113del​(p.Val705TrpfsTer5) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. V705V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 5.27

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47476473-TG-T is Pathogenic according to our data. Variant chr2-47476473-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 1760.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47476473-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2113del	p.Val705TrpfsTer5	frameshift_variant	13/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2113del	p.Val705TrpfsTer5	frameshift_variant	13/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 26, 2022	The c.2113delG pathogenic mutation, located in coding exon 13 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 2113, causing a translational frameshift with a predicted alternate stop codon (p.V705Wfs*5). This mutation has been detected in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several with family histories meeting Amsterdam criteria (Jeon HM et al. Hum. Mutat., 1996;7:327-33; Moslein G et al. Hum Mol Genet, 1996 Sep;5:1245-52)(Lin X et al. Dig. Dis. Sci., 1999 Mar;44:553-9; Domingo E et al. J Med Genet, 2004 Sep;41:664-8; Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83; Coolbaugh-Murphy MI et al. Hum Mutat, 2010 Mar;31:317-24; Cloyd JM et al. J Gastrointest Cancer, 2018 Mar;49:93-96). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 18, 2022	This variant deletes 1 nucleotide in exon 13 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. This variant has been reported in multiple individuals and families affected with Lynch syndrome (PMID: 8723682, 8872463, 10080150, 18566915, 20052760, 29238914). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Lynch syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 07, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 04, 2022	This frameshift variant alters the translational reading frame of the MSH2 mRNA and causes the premature termination of MSH2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with hereditary nonpolyposis colorectal cancer (HNPCC) (PMID: 8723682 (2996), 8872463 (1996), 10080150 (1999), 15342696 (2004), 16237223 (2005), 20052760 (2010)). It has also been reported in individuals with Lynch Syndrome (PMID: 18566915 (2009), 29238914 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2022	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene, and segregates with disease in many affected individuals (Jeon et al. 1996; Moslein et al., 1996; Lin et al., 1999; Domingo et al., 2004; Hegde et al., 2005; Nilbert et al., 2009; Coolbaugh-Murphy et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20052760, 15342696, 29238914, 16237223, 10080150, 8872463, 18566915, 8723682, 30787465) -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 15, 2019

Variant summary: MSH2 c.2113delG (p.Val705TrpfsX5) 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 251476 control chromosomes. c.2113delG has been reported in the literature in multiple individuals affected with Lynch Syndrome (Moslein_1996, Lin_1999, Hegde_2005, Nilbert_2009, Coolbaugh-Murphy_2010). 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. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation introducing premature termination codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

This sequence change creates a premature translational stop signal (p.Val705Trpfs*5) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome and Lynch syndrome-related cancers (PMID: 8723682, 8872463, 18566915, 20052760). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1760). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63749811; hg19: chr2-47703612;