2-47480876-G-C

Variant names:

• chr2-47480876-G-C
• rs267608017
• NM_000251.3:c.2634+5G>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001406653.1(MSH2):​c.2579G>C​(p.Cys860Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_001406653.1 missense
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 6.24

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 2-47480876-G-C is Pathogenic according to our data. Variant chr2-47480876-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 91019.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47480876-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2634+5G>C		splice_region_variant, intron_variant	Intron 15 of 15	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2634+5G>C		splice_region_variant, intron_variant	Intron 15 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Aug 09, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18033691]. 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]. -

Mar 06, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Pathogenic:2

Sep 05, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.2634+5G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site, while one predicts the variant weakens a 5' donor site. Publications reported experimental evidence confirming that this variant disrupts the splice-donor site, resulting in exon 15 skipping, and a frame-shift at the protein level (Davoodi-Semiromi_2000, Barnetson_2008). The variant was absent in 253506 control chromosomes (gnomAD and publications). c.2634+5G>C has been reported in the literature in multiple individuals affected with Lynch Syndrome, including at least one family where the variant co-segregated with the disease; microsatellite instability with loss of the MSH2/MSH6 proteins in the associated tumor was also noted (e.g. Davoodi-Semiromi_2000, Casey_2005, Barnetson_2008, Thompson_2013, Mork_2019). These data indicate that the variant is very likely to be associated with disease. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Variant causes splicing aberration, 2 MSI-H tumours, co-segregation with disease & MAF 0.00 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Apr 06, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2634+5G>C intronic pathogenic mutation results from a G to C substitution 5 nucleotides after coding exon 15 in the MSH2 gene. This alteration has been reported in a Scottish family that met Amsterdam I criteria where the proband was diagnosed with colon cancer at age 37 and the tumor showed high microsatellite instability. Further RT-PCR and PTT analyses showed that this alteration led to the skipping of exon 15 (Davoodi-Semiromi A et al. Am. J. Med. Genet. 2000 Nov;95:49-52). This pathogenic mutation has also been reported in another family meeting Amsterdam I criteria in which the proband's tumor demonstrated high microsatellite instability and showed loss of MSH2 and MSH6 by IHC. In addition, conversion analysis showed that this mutation resulted in exon skipping in cDNA and low expression of the affected MSH2 allele (Casey G et al. JAMA. 2005 Feb;293:799-809). In another study, this mutation was detected in 1/932 colon cancer patients and was not detected in any of 1017 normal controls. The individual with this mutation met Amsterdam II criteria for HNPCC/Lynch syndrome with a MSI-H tumor that showed loss of MSH2 and MSH6 by IHC (Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74). In silico splice site analysis for this alteration is inconclusive; however, direct evidence is insufficient at this time (Ambry internal data). Of note, this mutation is also referred to as IVS15+5G>C in some literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Jul 15, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G to C nucleotide substitution at the +5 position of intron 15 of the MSH2 gene. This variant is also known as IVS15+5G>C in the literature. Functional RNA studies have shown that this variant causes out-of-frame skipping of exon 15, resulting in premature truncation (PMID: 11074494, 18033691). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with colorectal cancer, with some tumors shown to be DNA mismatch repair deficient (PMID: 11074494, 15713769, 16807412, 31101557). In one family, this variant segregated in 5 affected family members (PMID: 18033691). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 15 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Lynch syndrome (PMID: 11074494, 18033691). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS15+5G>C. ClinVar contains an entry for this variant (Variation ID: 91019). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 15, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 15713769, 18033691). For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast Pathogenic:1

Nov 09, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Uncertain	24
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608017; hg19: chr2-47708015;