rs281864944

Positions:

• chr2-47412469-CAA-C
• chr2-47412469-CAA-CA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.704_705del​(p.Lys235ArgfsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T234T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MSH2 NM_000251.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 8.97

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47412469-CAA-C is Pathogenic according to our data. Variant chr2-47412469-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 91182.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47412469-CAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.704_705del	p.Lys235ArgfsTer20	frameshift_variant	4/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.704_705del	p.Lys235ArgfsTer20	frameshift_variant	4/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251348 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459814 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726344

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 09, 2018	The p.Lys235fs variant in MSH2 has been reported in 3 individuals with Lynch syn drome-associated cancers (Mangold 2005, Syngal 1999) and been identified in 1/11 1640 European chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org; dbSNP rs281864944). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positio n 235 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozy gous loss of function of the MSH2 gene is an established disease mechanism in in dividuals with Lynch syndrome. In addition, this variant was classified as patho genic on Sep 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV00 0107721.2). In summary, this variant meets criteria to be classified as pathogen ic for Lynch syndrome in an autosomal dominant manner based upon presence in mul tiple affected individuals, low frequency in the general population, and the pre dicted impact on the protein. ACMG/AMP Criteria applied (Richards 2015): PVS1; P M2; PS4_Supporting. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2017	Variant summary: The MSH2 c.704_705delAA (p.Lys235Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1030C>T/ p.Gln344X; c.1147C>T/ p.Arg383X; c.1165C>T/ p.Arg389X; c.1189C>T/ p.Gln397X). In addition, the variant of interest has been reported as pathogenic in multiple affected individuals via publications (Mangold_IJC_2005; Syngal_MLH1_JAMA_1999) and in one reputable database. One in silico tool predicts a damaging outcome for this variant. The variant of interest is absent in a large, broad control population, ExAC in 121020 control chromosomes. Taken together, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 2021	The c.704_705delAA pathogenic mutation, located in coding exon 4 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 704 to 705, causing a translational frameshift with a predicted alternate stop codon (p.K235Rfs*20). This mutation has been identified in one family fulfilling Amsterdam II criteria (Syngal S et al. JAMA. 1999 Jul;282:247-53), as well as in one individual of German descent fulfilling Bethesda criteria (Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702). This mutation was also detected in an individual with a family history of urinary tract cancers (Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 01;29:193-199). In addition to the clinical data presented in the literature, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 29, 2019	This variant deletes 2 nucleotides in exon 4 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two suspected hereditary nonpolyposis colorectal cancer families (PMID: 10422993, 15849733) and a healthy control from a pancreatic case-control study (PMID: 29922827). This variant has been identified in 1/251348 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Lynch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jul 27, 2023

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

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2016

This deletion of two nucleotides in MSH2 is denoted c.704_705delAA at the cDNA level and p.Lys235ArgfsX20 (K235RfsX20) at the protein level. The normal sequence, with the bases that are deleted in braces, is ACAA[AA]GACA. The deletion causes a frameshift which changes a Lysine to an Arginine at codon 235, and creates a premature stop codon at position 20 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 c.704_705delAA has been identified in association with colon cancer (Syngal 1999, Mangold 2005). We consider this variant to be pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 07, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91182). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 10422993, 15849733). This variant is present in population databases (rs281864944, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Lys235Argfs*20) 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). -

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: rs281864944; hg19: chr2-47639608;