rs1553361289

Positions:

• chr2-47445641-CT-C

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.1373del​(p.Leu458Ter) 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: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.404

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 2-47445641-CT-C is Pathogenic according to our data. Variant chr2-47445641-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 525710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1373del	p.Leu458Ter	frameshift_variant	8/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1373del	p.Leu458Ter	frameshift_variant	8/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453636 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 723816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 26, 2020

Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has been reported in a family with Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 525710). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu458*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2019

The c.1373delT pathogenic mutation, located in coding exon 8 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 1373, causing a translational frameshift with a predicted alternate stop codon (p.L458*). A different MSH2 alteration (c.1373T>G) resulting in the same truncation has been reported in multiple families with Lynch syndrome (Liu B et al. Cancer Res. 1994 Sep;54:4590-4; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835), including an individual with Muir-Torre phenotype whose sebaceous tumor demonstrated loss of MSH2 by IHC (Mangold E et al. J. Med. Genet. 2004 Jul;41:567-72). Additionally, ovarian and endometrial cancer specimens from individuals with the c.1373T>G MSH2 mutation demonstrated microsatellite instability and loss of MSH2 protein expression, while normal tissue from these patients was MSS with present MSH2 protein (Ichikawa Y et al. Cancer Genet. Cytogenet. 1999 Jul;112:2-8). Of note, this mutation is designated as "458 TTA to TGA," L458X, and "hMSH2/458/TTA to TGA" 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)		0.010		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: rs1553361289; hg19: chr2-47672780;