2-47445644-T-G

Variant names:

• chr2-47445644-T-G
• rs63750521
• NM_000251.3:c.1373T>G

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.1373T>G​(p.Leu458*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 5.79

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 2-47445644-T-G is Pathogenic according to our data. Variant chr2-47445644-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 90640.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47445644-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1373T>G	p.Leu458*	stop_gained	Exon 8 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1373T>G	p.Leu458*	stop_gained	Exon 8 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:2

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 p.Leu458X variant was identified in 9 or 4078 proband chromosomes from individuals or families with Lynch syndrome or Muir-Torre syndrome (Ichikawa 1999, Liu 1994, Liu 2000, Mangold 2004, Mangold 2005, Mangold 2005, Salahshor 2001, Wahlberg 1997). Analyses of tumours from probands demonstrated microsatellite instability and/or loss of MSH2 by immunohistochemistry staining (Ichikawa 1999, Liu 2000, Mangold 2004, Mangold 2005, Salahshor 2001). The variant was also identified in dbSNP (ID: rs63750521), HGMD, “Mismatch Repair Genes Variant Database”, and the “InSiGHT Colon Cancer Database”. The p.Leu458X variant leads to a premature stop codon at position 458, which is predicted to lead to 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. -

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Coding sequence variation introducing premature termination codon -

Lynch syndrome 1 Pathogenic:1

Aug 01, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Pathogenic:1

Jul 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Liu et al., 1994; Wahlberg et al., 1997; Ichikawa et al., 1999; Mangold et al., 2004; Mangold et al., 2005); This variant is associated with the following publications: (PMID: 25525159, 17312306, 26681312, 16321766, 11304573, 15235030, 23741719, 26143115, 8062247, 8931714, 10432927, 16216036, 27601186, 9036882, 31615790) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 21, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L458* pathogenic mutation (also known as c.1373T>G), located in coding exon 8 of the MSH2 gene, results from a T to G substitution at nucleotide position 1373. This changes the amino acid from a leucine to a stop codon within coding exon 8. This mutation has been reported in multiple families with Lynch syndrome, including several meeting Amsterdam criteria and/or exhibiting loss of MSH2 protein expression on IHC (Mangold E et al. J Med Genet, 2004 Jul;41:567-72; Casey G et al. JAMA, 2005 Feb;293:799-809; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835). This mutation has been identified in individuals with features of Muir-Torre (Liu B et al. Cancer Res, 1994 Sep;54:4590-4) and in families with urinary tract cancers (Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199). 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.97
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs63750521; hg19: chr2-47672783;