rs63750393

Variant names:

• chr2-47471006-CAG-C
• rs63750393
• NM_000251.3:c.1705_1706delGA

Your query was ambiguous. Multiple possible variants found:

• chr2-47471006-CAG-C
• chr2-47471006-CAG-CAGAG

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.1705_1706delGA​(p.Glu569IlefsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). 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:11 U:1 O:1
• Conservation: PhyloP100: 9.22

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 2-47471006-CAG-C is Pathogenic according to our data. Variant chr2-47471006-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 36569.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47471006-CAG-C is described in Lovd as [Pathogenic]. Variant chr2-47471006-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1705_1706delGA	p.Glu569IlefsTer2	frameshift_variant	Exon 11 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1705_1706delGA	p.Glu569IlefsTer2	frameshift_variant	Exon 11 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:4

Jan 17, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

not provided Pathogenic:2 Uncertain:1

Aug 09, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This pathogenic variant is denoted MSH2 c.1705_1706delGA at the cDNA level and p.Glu569IlefsX2 (E569IfsX2) at the protein level. The normal sequence, with the bases that are deleted in braces, is AACA[GA]ATAT. The deletion causes a frameshift, which changes a Glutamic Acid to an Isoleucine at codon 569, and creates a premature stop codon at position 2 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.1705_1706delGA, also reported as c.1705delAG and c.1704_1705delAG, has been reported in several families with Lynch syndrome (Apessos 2005, Mangold 2005, Kurzawski 2006, Stulp 2008, Choi 2009, Walsh 2010, Bauer 2011, De Lellis 2013). We consider this variant to be pathogenic. -

Mar 03, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Lynch syndrome (PMIDs: 34178123 (2021), 28874130 (2017), 28449805 (2017), 24278394 (2013), 20587412 (2010), 20007843 (2010), 19698169 (2009), 18759827 (2008), 15849733 (2005), 10777691 (2000)), breast cancer (PMIDs: 20215533 (2010), 16311127 (2005)), endometrial cancer (PMID: 15655560 (2005)), prostate cancer (PMID: 20872076 (2011)), and urinary tract cancer (PMID: 31615790 (2020)). Based on the available information, this variant is classified as pathogenic. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome Pathogenic:2

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Coding sequence variation introducing premature termination codon -

Aug 18, 2011

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

May 09, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1705_1706delGA pathogenic mutation, located in coding exon 11 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 1705 to 1706, causing a translational frameshift with a predicted alternate stop codon (p.E569Ifs*2). This mutation has been detected in multiple individuals and families affected with HNPCC/Lynch syndrome (Wijnen J et al. Am. J. Hum. Genet. 1997 Aug;61:329-35; Nomura S et al. Biochem. Biophys. Res. Commun. 2000 Apr;271:120-9; Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Westenend PJ et al. Hum. Pathol. 2005 Dec;36:1322-6; Kurzawski G et al. Clin. Genet. 2006 Jan;69:40-7; Julié C et al. Am. J. Gastroenterol. 2008 Nov;103:2825-35; quiz 2836; Sunga AY et al. Cancer Genet. 2017 Apr;212-213:1-7; Rossi BM et al. BMC Cancer 2017 Sep;17:623). A different alteration (c.1704_1705delAG) resulting in the same alternate stop codon was identified in probands with prostate and breast tumors showing absent MSH2 and MSH6 staining on IHC (Bauer CM et al. Fam. Cancer 2011 Mar;10:37-42; Walsh MD et al. Clin. Cancer Res. 2010 Apr;16:2214-24). 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. -

Jan 25, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides in exon 11 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with Lynch syndrome-associated cancer (PMID: 10404063, 10777691, 12414824, 15655560, 15713769, 15849733, 16311127, 16451135, 18759827, 19698169, 19706203, 20215533, 20587412, 20872076, 24278394, 28449805). 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. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu569Ilefs*2) 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 breast cancer and prostate cancer and a family history of colorectal, duodenal and prostate cancer and Lynch syndrome (PMID: 11920650, 15655560, 15713769, 15849733, 16311127, 19698169, 20215533, 20587412, 20872076, 24278394). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. This variant is also known as c.1704_1705delAG. ClinVar contains an entry for this variant (Variation ID: 36569). For these reasons, this variant has been classified as Pathogenic. -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750393; hg19: chr2-47698145;