rs63751482

chr2-47403324-GCGCACGGCGAGGACGCGCTGCTGGCCGCC-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000251.3(MSH2):c.136_164del(p.His46GlyfsTer26) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A45A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 8.54

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-47403324-GCGCACGGCGAGGACGCGCTGCTGGCCGCC-G is Pathogenic according to our data. Variant chr2-47403324-GCGCACGGCGAGGACGCGCTGCTGGCCGCC-G is described in ClinVar as [Pathogenic]. Clinvar id is 90639.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47403324-GCGCACGGCGAGGACGCGCTGCTGGCCGCC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.136_164del	p.His46GlyfsTer26	frameshift_variant	1/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.136_164del	p.His46GlyfsTer26	frameshift_variant	1/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.His46GlyfsX26 deletion has been previously reported in the literature in individuals with Lynch syndrome (Selected publications: Casey 2005, Choi 2009). This deletion is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 46 and leads to a premature stop 26 codons downstream. This alteration is predicted to lead to a truncated or absent protein product and loss of function. Loss of function variants are an established disease mechanism for the MSH2 gene and is the type of alteration expected to cause Lynch syndrome. In summary, based on the above information, this variant is classified as pathogenic. -

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 26, 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 premature termination codon -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs63751482; hg19: chr2-47630463;