2-47480812-G-T

Position:

• chr2-47480812-G-T

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.2575G>T​(p.Glu859*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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: 31)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 1.25

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]

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 2-47480812-G-T is Pathogenic according to our data. Variant chr2-47480812-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 91004.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47480812-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2575G>T	p.Glu859*	stop_gained	15/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2575G>T	p.Glu859*	stop_gained	15/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation introducing premature termination codon -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Glu859X variant was identified in the literature in an individual with suspected Lynch syndrome (Mangold 2005). The variant was also identified in dbSNP (ID: rs63749830) “With pathogenic allele”, HGMD, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database, and the ClinVar database (classified as pathogenic by InSiGHT). The p.Glu859X variant leads to a premature stop codon at position 859, 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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 15, 2020	This variant changes 1 nucleotide in exon 15 of the MSH2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 18, 2022	The p.E859* pathogenic mutation (also known as c.2575G>T), located in coding exon 15 of the MSH2 gene, results from a G to T substitution at nucleotide position 2575. This changes the amino acid from a glutamic acid to a stop codon within coding exon 15. This alteration was reported in a study of 1721 unrelated patients who met Bethesda criteria (Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702). A 42 year old patient with proximal colorectal cancer and loss of MSH2 expression on IHC was found to have this variant (Nagasaka T et al. Cancer Res. 2010 Apr;70:3098-108). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

MSH2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2024

The MSH2 c.2575G>T variant is predicted to result in premature protein termination (p.Glu859*). This variant was reported in an individual with hereditary non-polyposis colorectal cancer and in an individual with proximal colorectal cancer, loss of MSH2 protein expression, and somatic hypermethylation in the MSH2 promoter (Mangold et al. 2005. PubMed ID: 15849733; Nagasaka et al. 2010. PubMed ID: 20388775). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in MSH2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 09, 2023

This variant is considered pathogenic. This variant creates a termination codon and is 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

Dec 15, 2022

This sequence change creates a premature translational stop signal (p.Glu859*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91004). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 15849733, 20388775). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	35
DANN	Uncertain	0.97
Eigen	Benign	0.043
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.24	N
Vest4		0.77
GERP RS		0.10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs63749830; hg19: chr2-47707951; COSMIC: COSV51886024;