2-47480876-G-C

Position:

• chr2-47480876-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 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:7
• 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]

MSH2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2634+5G>C		splice_region_variant, intron_variant		ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2634+5G>C		splice_region_variant, intron_variant		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:7

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 06, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 09, 2023	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]. -

Lynch syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Variant causes splicing aberration, 2 MSI-H tumours, co-segregation with disease & MAF 0.00 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2019	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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 15, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 06, 2022	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. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 22, 2023

For these reasons, this variant has been classified as Pathogenic. 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 introduces a premature termination codon (PMID: 15713769, 18033691). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 91019). This variant is also known as IVS15+5G>C. 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 disrupted 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. -

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;