rs267607940

Variant names:

• chr2-47416430-G-A
• rs267607940
• NM_000251.3:c.1076+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47416430-G-A
• chr2-47416430-G-C
• chr2-47416430-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.1076+1G>A variant causes a splice donor, intron 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, intron
• 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 18 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
• 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 rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1076+1G>A		splice_donor_variant, intron_variant	Intron 6 of 15	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1076+1G>A		splice_donor_variant, intron_variant	Intron 6 of 15	1	NM_000251.3	ENSP00000233146.2

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

Oct 23, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Feb 14, 2020

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.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. -

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 -

not provided Pathogenic:2

Jun 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 20, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant demonstrated to result in aberrant splicing and predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 16395668, 31366136); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 21404117, 16034045, 31830689, 16395668, 25525159, 25980754, 19723918, 20587412, 15955785, 10480359, 21642682, 28449805, 29360550, 29887214, 31615790, 34178123, 30787465, 36243179, 36169650, 31366136) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Oct 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. 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). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 05, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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;