rs63750474

Positions:

• chr2-47471001-TAAAAC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000251.3(MSH2):​c.1700_1704del​(p.Lys567ArgfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000421 in 1,423,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 4.46

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-47471001-TAAAAC-T is Pathogenic according to our data. Variant chr2-47471001-TAAAAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 90755.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47471001-TAAAAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1700_1704del	p.Lys567ArgfsTer3	frameshift_variant	11/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1700_1704del	p.Lys567ArgfsTer3	frameshift_variant	11/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000421 AC: 6 AN: 1423666 Hom.: 0 AF XY: 0.00000422 AC XY: 3 AN XY: 710894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000557

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 03, 2023

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation introducing premature termination codon -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 16, 2015

This deletion of 5 nucleotides in MSH2 is denoted c.1700_1704delAAACA at the cDNA level and p.Lys567ArgfsX3 (K567RfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AATA[AAACA]GAAT. The deletion causes a frameshift, which changes a Lysine to an Arginine at codon 567, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 Lys567ArgfsX3 has been observed in at least one family presenting with the Muir-Torre variant of Lynch syndrome (Kruse 1996, Mangold 2004). we consider this variant to be pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90755). This variant is also known as 1699delAAACA and 1700-4del. This premature translational stop signal has been observed in individual(s) with Lynch syndrome or Muir-Torre syndrome (PMID: 8931714, 11208710, 11606497). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys567Argfs*3) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2024

The c.1700_1704delAAACA pathogenic mutation, located in coding exon 11 of the MSH2 gene, results from a deletion of 5 nucleotides at nucleotide positions 1700 to 1704, causing a translational frameshift with a predicted alternate stop codon (p.K567Rfs*3). This mutation has been reported in multiple individuals diagnosed with MSH2-deficient and/or microsatellite unstable colorectal cancer (Terdiman et al. Gastroenterology. 2001 Jan;120(1):21-30; Samowitz WS et al. Gastroenterology. 2001 Oct;121:830-8; Ambry internal data), as well as in an individual diagnosed with Muir-Torre syndrome (Mangold E et al. J Med Genet. 2004 Jul;41(7):567-72). Of note, this mutation is also designated as 1699del5 and 1700-4del in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted 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: rs63750474; hg19: chr2-47698140;