rs267607978

chr2-47475076-CTGT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP5_Moderate

The NM_000251.3(MSH2):c.1815_1817del(p.Val606del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.67

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 13 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000251.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-47475076-CTGT-C is Pathogenic according to our data. Variant chr2-47475076-CTGT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90793.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1815_1817del	p.Val606del	inframe_deletion	12/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1815_1817del	p.Val606del	inframe_deletion	12/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2019

The c.1815_1817delTGT variant (also known as p.V606del) is located in coding exon 12 of the MSH2 gene. This variant results from an in-frame TGT deletion between nucleotide positions 1815 and 1817. The valine at codon 606 is deleted. This variant was first identified in a patient who met Bethesda criteria and was diagnosed with endometrial complex atypical hyperplasia (CAH), endometrial adenocarcinoma (EC), and ovarian carcinoma at the age of 50. The patient was also diagnosed with multiple colorectal carcinomas, but the age at each diagnosis was not available. MSI and IHC analysis performed on tumor tissue from CAH and EC showed MSI-H and loss of MSH2 expression with no loss of MLH1 expression (Sutter C et al. Int. J. Gynecol. Pathol. 2004 Jan; 23(1):18-25). This variant was also detected by traditional sequencing techniques as well as SNP genotyping in one patient whose tumor tissue displayed microsatellite instability (Bujalkova M et al. Clin. Chem. 2008 Nov; 54(11):1844-54). The variant is deleterious using an evolution-based in silico predictor, PROVEAN, and this amino acid position is highly conserved in available vertebrate species (Choi Y et al. PLoS ONE 2012;7(10):e46688). Based on internal structural analysis, this variant sits in the lever region of MSH2 and is anticipated to result in a significant decrease in structural stability (Warren JJ et al. Mol. Cell 2007 May; 26(4):579-92 and Mukherjee S et al. Biophys. J. 2009 Mar; 96(5):1707-20). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs267607978; hg19: chr2-47702215;