chr2-47429740-A-G

Variant names:

• chr2-47429740-A-G
• rs267607943
• NM_000251.3:c.1077-2A>G

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.1077-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 8.36

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47429740-A-G is Pathogenic according to our data. Variant chr2-47429740-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90529.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47429740-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1077-2A>G		splice_acceptor_variant, intron_variant	Intron 6 of 15	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1077-2A>G		splice_acceptor_variant, intron_variant	Intron 6 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

MSH2-related disorder Pathogenic:1

Apr 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 c.1077-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in individuals with non-polyposis colorectal cancer (Mangold et al. 2005. PubMed ID: 15849733; Fatemi et al. 2023. PubMed ID: 37314251; Nagasaka et al. 2010. PubMed ID: 20388775) and a family history of urinary tract cancer (Wischhusen et al. 2019. PubMed ID: 31615790). Alternative splicing variants (c.1077-2A>C and c.1077-2A>T), have been reported to be pathogenic. This variant has not been reported in a large population database, indicating this variant is rare. It is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/90529/). Variants that disrupt the consensus splice acceptor site in MSH2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Lynch syndrome 1 Pathogenic:1

Jul 31, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. -

Lynch syndrome Pathogenic:1

Jun 21, 2019

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Interrupts canonical donor splice site -

not provided Pathogenic:1

May 08, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.1077-2A>G variant (rs267607943) is reported in the literature in multiple individuals affected with Lynch syndrome (Mueller-Koch 2005, Mangold 2005, Nagasaka 2010, Wischhusen 2020). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron 6, which is likely to negatively impact gene function. Additionally, different variants at this splice acceptor site (c.1077-2A>G, c.1077-2A>T, c.1077-1G>A, c.1077-1G>T and c.1077-1G>C) have been reported in individuals with Lynch syndrome. Based on available information, this variant is considered to be likely pathogenic. References Mueller-Koch et al. Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut. 2005 Dec;54(12):1733-40. PMID: 15955785 Mangold E et al. Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. Int J Cancer. 2005 Sep 20;116(5):692-702. PMID: 15849733 Nagasaka T et al. Somatic hypermethylation of MSH2 is a frequent event in Lynch Syndrome colorectal cancers. Cancer Res. 2010 Apr 15;70(8):3098-108. PMID: 20388775 Wischhusen JW et al. Clinical Factors Associated with Urinary Tract Cancer in Individuals with Lynch Syndrome. Cancer Epidemiol Biomarkers Prev. 2020 Jan;29(1):193-199. PMID: 31615790 -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 6 of the MSH2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome-associated cancers (PMID: 15849733, 15955785, 20388775, 24278394, 37314251; internal data). ClinVar contains an entry for this variant (Variation ID: 90529). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 18, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1077-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 7 in the MSH2 gene. This intronic mutation has previously been reported in a German patient whose personal and family history was suspicious for HNPCC/Lynch syndrome and whose tumor was MSI-H with absent MSH2/MSH6 proteins on IHC, as well as a patient with endometrial cancer whose tumor had absent MSH2/MSH6 proteins on IHC with a family history meeting Amsterdam criteria (Mueller-Koch Y et al. Gut 2005 Dec;54(12):1733-40; Ambry internal data). This variant was also reported in a male proband age 47 with a family history of urinary tract cancers (Wischhusen JW et al. Cancer Epidemiol Biomarkers Prev, 2020 Jan;29:193-199). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.94		Position offset: 13
DS_AL_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607943; hg19: chr2-47656879; COSMIC: COSV51879494;