rs63750586

chr2-47429867-T-TA

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.1203dup(p.Gln402ThrfsTer15) variant causes a frameshift change involving the alteration of a non-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:5
• Conservation: PhyloP100: 0.884

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 2-47429867-T-TA is Pathogenic according to our data. Variant chr2-47429867-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 90564.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1203dup	p.Gln402ThrfsTer15	frameshift_variant	7/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1203dup	p.Gln402ThrfsTer15	frameshift_variant	7/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 23, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 27, 2016	- -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation introducing a premature termination codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 28, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has been reported in individuals affected with Lynch syndrome (PMID: 20591884, 17453009). ClinVar contains an entry for this variant (Variation ID: 90564). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln402Thrfs*15) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2022

The c.1203dupA pathogenic mutation, located in coding exon 7 of the MSH2 gene, results from a duplication of A at nucleotide position 1203, causing a translational frameshift with a predicted alternate stop codon (p.Q402Tfs*15). This mutation has been reported in individuals with MSI-H early onset colorectal cancers demonstrating loss of MSH2 and MSH6 expression by IHC (Overbeek LI et al. Br. J. Cancer 2007 May;96:1605-12). This mutation has also been identified in Lynch syndrome patients with urothelial bladder cancer and endometrial cancer (van der Post RS et al. J. Med. Genet. 2010 Jul;47:464-70; Jóri B et al. Oncotarget 2015 Dec;6:41108-22). This alteration was one of two somatic MSH2 frameshift mutations identified in an MSI-H colon tumor with loss of MSH2 and MSH6 by IHC (Haraldsdottir S et al. Gastroenterology 2014 Dec;147:1308-1316.e1). Of note, this alteration is also designated as c.1203dup, p.Gln402fs, and p.Gln402Thrfs*15 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs63750586; hg19: chr2-47657006;