rs1114167851

chr2-47412403-TTTCAAAATAGATAA-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PP3 PP5_Moderate

The NM_000251.3(MSH2):c.646-4_655del 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: 32)
• Consequence: MSH2 NM_000251.3 splice_acceptor, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.62

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.052049913 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5, offset of -3, new splice context is: ttaaactatttctttcaaAGagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 2-47412403-TTTCAAAATAGATAA-T is Pathogenic according to our data. Variant chr2-47412403-TTTCAAAATAGATAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 428516.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.646-4_655del		splice_acceptor_variant, coding_sequence_variant, intron_variant	4/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.646-4_655del		splice_acceptor_variant, coding_sequence_variant, intron_variant	4/16	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: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2023

The c.646-4_655del14 pathogenic mutation spans the last four nucleotides of intron 3 (ATAG) through the first 10 nucleotides of coding exon 4 (ATAATTCAAA) in the MSH2 gene. This pathogenic mutation results from a deletion of 14 nucleotides and disrupts the canonical splice acceptor site. To our knowledge, this specific alteration has not been reported in the literature to date. However, a deletion of 12 nucleotides which disrupts the same splice acceptor site (c.646-5_654del12), has been reported in a German family with suspected HNPCC (Mangold E et al. Int. J. Cancer 2005 Sep;116(5):692-702). In silico splice site analysis predicts that this alteration will weaken the native acceptor site and may result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

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: rs1114167851; hg19: chr2-47639542;