rs587779157

Positions:

• chr2-47408485-GAGTTGA-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM4 PP3 PP5_Very_Strong

The NM_000251.3(MSH2):​c.301_306delGAAGTT​(p.Glu101_Val102del) 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 Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 8.66

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 Pathogenic. Variant got 13 ACMG points.

• 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
• PP5: Variant 2-47408485-GAGTTGA-G is Pathogenic according to our data. Variant chr2-47408485-GAGTTGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91060.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47408485-GAGTTGA-G is described in Lovd as [Likely_pathogenic]. Variant chr2-47408485-GAGTTGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.301_306delGAAGTT	p.Glu101_Val102del	conservative_inframe_deletion	2/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.301_306delGAAGTT	p.Glu101_Val102del	conservative_inframe_deletion	2/16	1	NM_000251.3	ENSP00000233146.2

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

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2019	Variant summary: MSH2 c.301_306delGAAGTT (p.Glu101_Val102del) results in an in-frame deletion that is predicted to remove 2 amino acids from the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein. The variant was absent in 251332 control chromosomes (gnomAD). c.301_306delGAAGTT has been reported in the literature in individuals affected with Lynch Syndrome (Latham_2019, Espenschied_2017, Goldberg_2008, Glasl_2000). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) through multifactorial analysis classified the variant as likely pathogenic (Thompson_2014). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1), likely pathogenic (n=3) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 21, 2019	Multifactorial likelihood analysis posterior probability 0.95-0.99 -
Pathogenic, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Apr 01, 2018	The MSH2 variant designated as NM_000251.2:c.301_306del is classified as likely pathogenic. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 1.99 to 1 (Thompson, et al., 2003, PMID:1290079), which provides some evidence that this allele is pathogenic. Multifactorial likelihood analysis from the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) database gives a 95% probability of pathogenicity for this variant as of the year 2016 (http://www.insight-database.org/classifications/). This variant is not found in the ExAC (exac.broadinstitute.org) or gnomAD (gnomad.broadinstitute.org) population databases or the UMD database (http://umd.be/). This genomic region is highly conserved across species. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a >99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is predicted to alter MSH2 function and increase cancer risk. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Lynch syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 21, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 27, 2022	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2016

This deletion of 6 nucleotides in MSH2 is denoted c.301_306delGAAGTT at the cDNA level and p.E101_V102del at the protein level. This deletion is also known as MSH2 c.297_302delAGTTGA or 300_305delAGTTGA using alternate nomenclature. The normal sequence, with the bases that are deleted in braces, is AGTT[GAAGTT]TATA. This in frame deletion occurs in a region which is conserved across species and is located within the mismatch binding domain (Lutzen 2008). This variant was observed in at least two patients with early onset colorectal cancer meeting Lynch criteria with tumor studies demonstrating microsatellite instability and immunohistochemistry absent for MSH2 protein (Glasl 2000, Goldberg 2008). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely pathogenic (Thompson 2014). Based on the currently available information, we consider MSH2 p.Glu101_Val102del to be a likely pathogenic variant. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 07, 2023

This variant, c.301_306del, results in the deletion of 2 amino acid(s) of the MSH2 protein (p.Glu101_Val102del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Lynch syndrome or clinical features of Lynch syndrome (PMID: 10874318, 11179758, 18389388; Invitae; externalcommunication). This variant is also known as 300-305delAGTTGA, 300delAGTTGA, c.297_302delAGTTGA. ClinVar contains an entry for this variant (Variation ID: 91060). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2023

The c.301_306delGAAGTT variant (also known as p.E101_V102del) is located in coding exon 2 of the MSH2 gene. This variant results from an in-frame six base pair deletion between nucleotide positions 301 and 306. This results in the deletion of a glutamic acid residue and a valine residue, two highly conserved amino acids, between codons 101 and 102. This alteration has been previously reported in multiple families meeting Amsterdam and/or Bethesda criteria and included family members with colon tumors that demonstrated absent MSH2 staining on immunohistochemistry and high microsatellite instability (MSI-H) (Glasl et al. Hum Mutat. 2000 Jul;16(1):91-2; Goldberg et al. Fam Cancer. 2008;7(4):309-17; Ambry internal data). This alteration has been classified as likely pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15). Of note, this variant is also referred to as 300-305delAGTTGA and c.297_302delAGTTGA in published literature. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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: rs587779157; hg19: chr2-47635624;