2-47429740-A-G

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):c.1077-2A>G variant causes a splice acceptor 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5
• 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 22 ACMG points.

• PVS1: Splicing 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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/exons	MANE	UniProt
MSH2	NM_000251.3	c.1077-2A>G		splice_acceptor_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1077-2A>G		splice_acceptor_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely 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.

Jul 31, 2023

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

Likely pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

Interrupts canonical donor splice site -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 08, 2021

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2023

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 disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Lynch syndrome-associated cancers (PMID: 15849733, 15955785, 20388775, 24278394, 37314251). 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 introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.1077-2G nucleotide in the MSH2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 14970868, 24278394, 31615790; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

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
MutationTaster	Benign	1.0	D;D;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;