chr2-47410294-TCTC-T

Variant names:

• chr2-47410294-TCTC-T
• rs587779165
• NM_000251.3:c.571_573delCTC

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000251.3(MSH2):​c.571_573delCTC​(p.Leu191del) 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L191L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 conservative_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 7.96
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 32 uncertain in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000251.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-47410294-TCTC-T is Pathogenic according to our data. Variant chr2-47410294-TCTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 91139.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.571_573delCTC	p.Leu191del	conservative_inframe_deletion	Exon 3 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.571_573delCTC	p.Leu191del	conservative_inframe_deletion	Exon 3 of 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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Apr 28, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of one amino acid in a non-repeat region; Observed in individuals with MSH2-related cancers, some of which demonstrated absence of MSH2 and/or MSH6 protein expression in tumors (PMID: 33003368, 20587412); Not observed at significant frequency in large population cohorts (gnomAD); Classified pathogenic by a well-established clinical consortium and/or database (InSiGHT); This variant is associated with the following publications: (PMID: 22949379, 24689082, 24362816, 26681312, 20587412, 19267393, 30787465, 18822302, 21120944, Tsukanov2023[CaseReport], 33003368, 30612635) -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH2: PS3, PM2, PP1:Moderate, PS4:Moderate, PM4:Supporting -

Carcinoma of colon Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 p.Leu191del variant was identified in 6 of 258 proband chromosomes (frequency: 0.023) from Norwegian individuals or families with inherited CRC/Lynch syndrome (Sjursen_2010). The variant was also identified in the following databases: dbSNP (ID: rs587779165) as With Pathogenic allele ,ClinVar (2x, as pathogenic by InSight, Ambry Genetics, 3x as likely pathogenic by GeneDx, Invitae, COGR, reviewed by expert panel), GeneInsight-COGR (as likely pathogenic), UMD-LSDB (2x, as causal), Insight Colon Cancer Gene Variant Database (2x, class 5), Insight Hereditary Tumors Database (2x, as class 5). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. Various bioinformatics tools (multifactorial likelihood model and 5-tiered scheme) applied to standardize the classification of MMR variants, classified the variant as pathogenic (Thompson 2013, Thompson 2014). In vitro analysis for splicing aberrations did not show the variant caused any splicing defect, but in silico models based on evolutionary conservation, causality and physiochemical properties, as well as segregation data, classified the variant as probably pathogenic (Arnold 2009). This variant is an in-frame deletion resulting in the removal of a leucine (Leu) residue at codon 191; the impact of this alteration on MSH2 protein function is not known. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. The variant is located with the DNA mismatch repair protein MutS, connector domain DNA mismatch repair protein, MSH2 functional domain(s) increasing the likelihood that it may have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Lynch syndrome 1 Pathogenic:1

Jun 28, 2023

Human Genetics Bochum, Ruhr University Bochum

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria used to clasify this variant:PS4, PM1, PM4, PM2_SUP, PP1 -

Lynch syndrome Pathogenic:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Multifactorial likelihood analysis posterior probability >0.99 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jun 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.571_573del, results in the deletion of 1 amino acid(s) of the MSH2 protein (p.Leu191del), 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 clinical features of Lynch syndrome (PMID: 19267393, 20587412, 22949379, 26681312). It has also been observed to segregate with disease in related individuals. Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 91139). 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

Mar 25, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.571_573delCTC pathogenic mutation (also known as p.L191del) is located in coding exon 3 of the MSH2 gene. This pathogenic mutation results from an in-frame deletion of 3 nucleotides between positions 571 and 573. This results in the deletion of a leucine residue at codon 191. This alteration has been classified as 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 BA et al. Nat. Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This mutation has also been reported in six unrelated HNPCC families, five of which had absent MSH2 and MSH6 staining on IHC (Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85). In addition, it was identified in 1/10030 patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=53/47	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587779165; hg19: chr2-47637433;