rs786204050

Positions:

• chr2-47478341-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000233146.7(MSH2):​c.2283del​(p.Leu762Ter) 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 (★). Synonymous variant affecting the same amino acid position (i.e. G761G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 ENST00000233146.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.33

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 12 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 2-47478341-TG-T is Pathogenic according to our data. Variant chr2-47478341-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 188073.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2283del	p.Leu762Ter	frameshift_variant	14/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2283del	p.Leu762Ter	frameshift_variant	14/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 10, 2014

This sequence change deletes 1 nucleotide in exon 14 of the MSH2 mRNA (c.2281delG), creating a premature translational stop signal at codon 762 (p.Leu762*). It is expected to result in an absent or disrupted protein product. While this particular sequence change has not been reported in the literature, truncating sequence changes in MSH2 are known to be pathogenic (PMID: 15849733). This is a novel sequence change that is expected to disrupt MSH2 protein function. For these reasons, this sequence change has been classified as Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 10, 2014

This sequence change deletes 1 nucleotide in exon 14 of the MSH2 mRNA (c.2281delG), creating a premature translational stop signal at codon 762 (p.Leu762*). It is expected to result in an absent or disrupted protein product. This is a novel sequence change that is expected to disrupt MSH2 protein function. For these reasons, this sequence change has been classified as Pathogenic. While this particular sequence change has not been reported in the literature, truncating sequence changes in MSH2 are known to be pathogenic (PMID: 15849733). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs786204050; hg19: chr2-47705480;