rs267607957

chr2-47445658-G-Achr2-47445658-G-Cchr2-47445658-G-T

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.1386+1G>A variant causes a splice donor change. 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: 33)
• Consequence: MSH2 NM_000251.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.20

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 2-47445658-G-A is Pathogenic according to our data. Variant chr2-47445658-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90641.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47445658-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-47445658-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1386+1G>A		splice_donor_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1386+1G>A		splice_donor_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The c.1386+1G>A variant was identified in 3 of 3562 proband chromosomes (frequency: 0.001) from individuals or families with Lynch Syndrome (Auclair, 2006; Mangold, 2005). The variant was also identified in dbSNP (ID: rs267607957) “With pathogenic allele”, HGMD, “MMR Gene Unclassified Variants Database”, “InSiGHT Colon Cancer Database” (as likely pathogenic), and the ClinVar database. The c.1386+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. Studies by Auclair and Betz have shown this variant to cause the loss of exon 8 and Mueller-Koch links this loss to a loss of expression of the MSH2 protein in colon tumours. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing in 4 of 5 programs. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 21, 2019	Interrupts canonical donor splice site -

Hereditary nonpolyposis colon cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 12, 2020

Variant summary: MSH2 c.1386+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. Publications reported experimental evidence, demonstrating that the variant resulted in the skipping of exon 8 (Auclair_2006, Betz_2010). The variant was absent in 248984 control chromosomes (gnomAD). c.1386+1G>A has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Auclair_2006, Mangold_2005, Mueller-Koch_2005, Betz_2010, Baert-Desurmont_2018, Jiang_2019). These data indicate that the variant is likely to be associated with disease. Three other submitters, including an expert panel (InSiGHT), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (2x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Lynch syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 01, 2023

This variant is considered likely 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. -

Hereditary nonpolyposis colorectal carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Medical Genetics, Medical University Pleven

Jan 01, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2023

This sequence change affects a donor splice site in intron 8 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 (PMID: 15849733, 16736289). ClinVar contains an entry for this variant (Variation ID: 90641). Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (PMID: 16395668, 19669161; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 13, 2021

The c.1386+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the MSH2 gene. This mutation has been previously identified in individuals with personal and/or family histories suggestive of Lynch syndrome (Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Mueller-Koch Y et al. Gut 2005 Dec;54:1733-40; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). This mutation has been identified as somatic in conjunction with a somatic pathogenic MSH2 variant in a Lynch syndrome-associated tumor that demonstrated loss of MSH2/MSH6 expression by immunohistochemistry (IHC; Watkins JC et al. Int. J. Gynecol. Pathol. 2017 Mar;36:115-127). This variant has been identified in probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH2 or MSH2/MSH6 expression by IHC (Ambry internal data). Additionally, functional analyses have demonstrated that this alteration leads to the skipping of coding exon 8 (Auclair J et al. Hum. Mutat. 2006 Feb;27:145-54; Betz B et al. J. Cancer Res. Clin. Oncol. 2010 Jan;136:123-34; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor 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	0.40
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607957; hg19: chr2-47672797;