2-47416430-G-A

Position:

• chr2-47416430-G-A

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.1076+1G>A variant causes a splice donor 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 Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.81

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 +-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
• 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 2-47416430-G-A is Pathogenic according to our data. Variant chr2-47416430-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 90519.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47416430-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1076+1G>A		splice_donor_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1076+1G>A		splice_donor_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

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]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 23, 2023	- -

Lynch syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2020	Variant summary: MSH2 c.1076+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. These predictions were confirmed by publications reporting experimental evidence demonstrating that this variant results in exon 6 skipping, which is predicted to result in a frame-shift at the protein level (Auclair_2006, Fernandez-Rozadilla_2019). The variant was absent in 251386 control chromosomes (gnomAD). The variant, c.1076+1G>A, has been reported in the literature in multiple individuals affected with Lynch Syndrome and related tumor phenotypes (e.g. Wang_1999, Fernandez-Rozadilla_2019). Four submitters, including one expert panel (InSiGHT) have provided clinical-significance assessments for this variant in ClinVar, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2016	This variant is denoted MSH2 c.1076+1G>A or IVS6+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 6 of the MSH2 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Consistent with splicing predictions, this variant was observed to result in skipping of exon 6 using an RT-PCR assay (Auclair 2006). This variant has been reported in several families whose cancer histories are consistent with Lynch Syndrome (Wang 1999, Bonadona 2011, Stormorken 2005, Sjursen 2010, Mueller-Koch 2005). In addition, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). Based on the current evidence, we consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 09, 2023	The MSH2 c.1076+1G>A variant disrupts a canonical splice-donor site and interferes with normal MSH2 mRNA splicing. This variant has been reported in the published literature in several individuals and families affected with Lynch syndrome associated cancers including colorectal cancer (PMIDs: 10480359 (1999), 15955785 (2005), 16034045 (2005), 16395668 (2006), 20587412 (2010), 29360550 (2018), 31366136 (2019)), prostate cancer (PMID: 19723918 (2009)), and ovarian cancer (PMID: 36169650 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 04, 2023

This sequence change affects a donor 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 clinical features of Lynch syndrome (PMID: 10480359, 15955785, 19723918, 21642682, 28449805, 31366136). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90519). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16395668, 31366136; Invitae). 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

Apr 05, 2023

The c.1076+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 6 of the MSH2 gene. This mutation has been identified in multiple individuals that met Amsterdam I/II criteria for Lynch syndrome and/or had tumors that demonstrated loss of MSH2/MSH6 expression on immunohistochemistry (Ambry internal data; Wang Q et al. Hum Genet 1999;105:79-85; Stormorken AT et al. J. Clin. Oncol., 2005 Jul;23:4705-12; Mueller-Koch Y et al. Gut, 2005 Dec;54:1733-40; Sjursen W et al. J. Med. Genet., 2010 Sep;47:579-85; Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Sunga AY et al. Cancer Genet, 2017 Apr;212-213:1-7; Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29; Wardell CP et al. J. Hepatol., 2018 05;68:959-969; Fernandez-Rozadilla C et al. Cancers (Basel), 2019 Jul;11:1081; Yang M et al. Ther Adv Med Oncol, 2021 Jun;13:17588359211023290). This alteration has also been shown to result in exon skipping by mRNA analysis (Auclair J et al. Hum Mutat. 2006; 27:145-54; Fernandez-Rozadilla C et al. Cancers (Basel), 2019 Jul;11:1081). 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. -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		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: rs267607940; hg19: chr2-47643569;