rs1553369194

Positions:

• chr2-47476539-GGCTGAAATGTTGGAAACT-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4 PP3

The NM_000251.3(MSH2):​c.2182_2199delGAAATGTTGGAAACTGCT​(p.Glu728_Ala733del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.60

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a helix (size 14) in uniprot entity MSH2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2182_2199delGAAATGTTGGAAACTGCT	p.Glu728_Ala733del	conservative_inframe_deletion	13/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2182_2199delGAAATGTTGGAAACTGCT	p.Glu728_Ala733del	conservative_inframe_deletion	13/16	1	NM_000251.3	ENSP00000233146.2

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: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Glu728_Ala733del variant was identified in 1 of 102 proband chromosomes (frequency: 0.01) from individuals or families with Lynch Syndrome tumours and predicted to have an effect on protein function (Barrow 2010). The variant was not identified in dbSNP NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (released January 13, 2015), COSMIC, MutDB, Mismatch Repair Genes Variant, MMR Gene Unclassified Variants , InSiGHT Colon Cancer Database, Zhejiang Colon Cancer, the ClinVar, Clinvitae, GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) and UMD databases. This variant is an in-frame deletion resulting in the removal of 5 amino acids from Glu residue at codon 728 to Ala residue at codon 733. The presence of a Lynch syndrome related cancer in this individual and in other family members is supportive of a pathogenic role for this variant. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic. -

Lynch syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Feb 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553369194; hg19: chr2-47703678;