chr2-47482800-G-T

Position:

• chr2-47482800-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.2656G>T​(p.Glu886*) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 4.70

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]

MSH2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47482800-G-T is Pathogenic according to our data. Variant chr2-47482800-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 433904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47482800-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.2656G>T	p.Glu886*	stop_gained	16/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2656G>T	p.Glu886*	stop_gained	16/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

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 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

Apr 24, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Leu888Cysfs*4) have been determined to be pathogenic (PMID: 9222765, 9774676, 17531815, 18822302; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 433904). This premature translational stop signal has been observed in individual(s) with Lynch syndrome-associated cancers (PMID: 27413415). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Glu886*) in the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the MSH2 protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2022

The p.E886* variant (also known as c.2656G>T), located in coding exon 16 of the MSH2 gene, results from a G to T substitution at nucleotide position 2656. This changes the amino acid from a glutamic acid to a stop codon within coding exon 16. This alteration occurs at the 3' terminus of theMSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 49 amino acids of the protein. However, premature stop codons are typically deleterious in nature, and a significant portion of the protein is affected. This variant was reported to co-segregate with disease in a family that met Amsterdam II criteria for Lynch syndrome, and several family members had tumors that demonstrated loss of both MSH2/MSH6 protein expression (Rashid MU et al. Hered Cancer Clin Pract, 2016 Jul;14:14; Rashid MU et al. Hered Cancer Clin Pract, 2019 Oct;17:29). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	45
DANN	Uncertain	0.99
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.85
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.28		Position offset: -21

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

Publications

LitVar

Other links and lift over

dbSNP: rs1230083633; hg19: chr2-47709939;