rs1553350052

chr2-47408396-TTAAGGAGCAAAGAATCTGCAGAGTGTTGTGCTTAGTAAAATGAATTTTGAATCTTTTGTAAAAGATCTTCTTCTGGTTCGTCAGTATAGAGTTGAAGTTTATAAGAATAGAGCTGGAAATAAGGCATCCAAGGAGAATGATTGGTATTTGGCATA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PP3 PP5_Moderate

The NM_000251.3(MSH2):c.213_366+1del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 splice_acceptor, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.49

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 11 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 2-47408396-TTAAGGAGCAAAGAATCTGCAGAGTGTTGTGCTTAGTAAAATGAATTTTGAATCTTTTGTAAAAGATCTTCTTCTGGTTCGTCAGTATAGAGTTGAAGTTTATAAGAATAGAGCTGGAAATAAGGCATCCAAGGAGAATGATTGGTATTTGGCATA-T is Pathogenic according to our data. Variant chr2-47408396-TTAAGGAGCAAAGAATCTGCAGAGTGTTGTGCTTAGTAAAATGAATTTTGAATCTTTTGTAAAAGATCTTCTTCTGGTTCGTCAGTATAGAGTTGAAGTTTATAAGAATAGAGCTGGAAATAAGGCATCCAAGGAGAATGATTGGTATTTGGCATA-T is described in ClinVar as [Pathogenic]. Clinvar id is 433875.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.213_366+1del		splice_acceptor_variant, coding_sequence_variant, intron_variant	2/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.213_366+1del		splice_acceptor_variant, coding_sequence_variant, intron_variant	2/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lynch syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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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: rs1553350052; hg19: chr2-47635535;