rs267607970

chr2-47470964-G-Achr2-47470964-G-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):c.1662-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.22

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 20 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• 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 2-47470964-G-A is Pathogenic according to our data. Variant chr2-47470964-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 90727.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47470964-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1662-1G>A		splice_acceptor_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1662-1G>A		splice_acceptor_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1278470 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 645932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Variant causes splicing aberration (full inactivation of variant allele) -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 10, 2017	The c.1662-1G>A variant in MSH2 has been reported as a germline variant in the h omozygous state in 1 individual with T-cell acute lymphoblastic leukemia and mul tiple cafe-au-lait spots (Whiteside 2002) and was absent in large population stu dies. This variant occurs in the invariant region (+/- 1,2) of the splice consen sus sequence and has shown to cause exon 11 skipping in blood derived patient RN A and results in an absent MSH2 protein (Whiteside 2002). Heterozygous loss of f unction of the MSH2 gene is an established disease mechanism in individuals with Lynch syndrome. Furthermore, the c.1662-1G>A variant has been classified as pat hogenic on Sept. 5th, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107248.2). In summary, this variant meets criteria to be classified as pa thogenic for Lynch syndrome in an autosomal dominant manner based upon impact to the protein, functional studies and absence from controls. -

Lynch syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Aug 03, 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. -

Lynch-like syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Constitutional Genetics Lab, Leon Berard Cancer Center

Jul 01, 2019

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 18, 2022

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 11809679, 24090359). ClinVar contains an entry for this variant (Variation ID: 90727). Disruption of this splice site has been observed in individual(s) with MSH2-related conditions (PMID: 11809679, 28944238). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 10 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2019

The c.1662-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 11 of the MSH2 gene. A 2 year old child with leukemia and multiple cafe´-au-lait spots was reported to be homozygous for c.1662-1G>A. Analysis of RNA from this patient confirmed skipping of exons 11 and 12 resulting in a truncated, nonfunctional protein. Furthermore, Western blot analysis on total protein extracts isolated from the LCLs showed lack of MSH2 protein (Whiteside D et al. Cancer Res. 2002 Jan; 62(2):359-62). This mutation was identified in 1/333 individuals with early onset colon cancer and in 0/93 unaffected controls (DeRycke MS et al. Mol Genet Genomic Med 2017 Sep;5:553-569). Tumor molecular phenotype and mutation data also supports pathogenicity of this variant (Shirts BH et al. Am. J. Hum. Genet. 2018 Jul;103:19-29). This nucleotide position is highly conserved in available vertebrate species. 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. -

Mismatch repair cancer syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	30
Dann	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		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: rs267607970; hg19: chr2-47698103;