rs63751142

Positions:

• chr2-47429886-C-CT
• chr2-47429886-C-CTT

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.1222dupT​(p.Tyr408fs) 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:7
• Conservation: PhyloP100: 7.25

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]

MSH2 (HGNC:):

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 2-47429886-C-CT is Pathogenic according to our data. Variant chr2-47429886-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 90573.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1222dupT	p.Tyr408fs	frameshift_variant	7/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1222dupT	p.Tyr408fs	frameshift_variant	7/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2016	This duplication of one nucleotide in MSH2 is denoted c.1222dupT at the cDNA level and p.Tyr408LeufsX9 (Y408LfsX9) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is ACTC[dupT]ATCA. The duplication causes a frameshift which changes a Tyrosine to a Leucine at codon 408, and creates a premature stop codon at position 9 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.1222dupT has been reported in association with Lynch syndrome (Casey 2005). We consider this variant to be pathogenic. -

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Tyr408LeufsX9 variant was identified in 7 of 4808 proband chromosomes (frequency: 0.001) from individuals or families with Lynch Syndrome (Casey 2005, Holinski-Feder 2001, Mangold 2005, Mueller-Koch 2005, Parc 2003, Wolf 2005). Tumour samples from two of these probands showed loss of MSH2 protein expression, and additional testing of one tumour showed high microsatellite instability (Casey 2005, Mueller-Koch 2005). The variant was also identified in dbSNP (ID: rs63751142), HGMD, UMD (14X as a causal variant), “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database, and the ClinVar Database (classified as pathogenic by InSiGHT). The p.Tyr408LeufsX9 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 408 and leads to a premature stop codon 9 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. -

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 01, 2023

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

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 16, 2021

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90573). This variant is also known as c.1223insT, c.1222_1223insT. This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12624141, 15713769, 15849733, 15926618, 15955785). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr408Leufs*9) 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2024

The c.1222dupT pathogenic mutation, located in coding exon 7 of the MSH2 gene, results from a duplication of T at nucleotide position 1222, causing a translational frameshift with a predicted alternate stop codon (p.Y408Lfs*9). This mutation has been reported in several individuals and families suspected of Lynch syndrome based on personal and/or family history. The tumors of multiple probands have demonstrated high microsatellite instability and/or loss of MSH2 expression on IHC (Casey G et al. JAMA. 2005 Feb;293:799-809; Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702; Mueller-Koch Y et al. Gut. 2005 Dec;54:1733-40; Parc Y et al. J. Med. Genet. 2003 Mar;40:208-13; Wolf B et al. Wien. Klin. Wochenschr. 2005 Apr;117:269-77). Of note, this alteration is also designated as 1222insT, 1223insT, and 1222_1223inT 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)		0.080		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: rs63751142; hg19: chr2-47657025;