rs267608006

chr2-47478262-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):c.2211-10T>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.32

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 14 ACMG points.

• 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 2-47478262-T-A is Pathogenic according to our data. Variant chr2-47478262-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 90927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2211-10T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2211-10T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251118 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135724

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461242 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726810

Gnomad4 AFR exome AF: 0.0000299

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.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 28, 2023	This variant causes a T to A nucleotide substitution at the -10 position of intron 13 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Lynch syndrome-associated cancers (communication with external laboratories; ClinVar SCV000580509.6, SCV000260343.7). This variant has also been reported in the literature in an individual affected with Muir-Torre syndrome with a family history of colorectal and esophageal cancer, and the proband's tumor showed lack of MSH2 and MSH6 protein expression (PMID: 17199584). This variant has been identified in 1/251118 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 15, 2024	The c.2211-10T>A intronic variant results from a T to A substitution 10 nucleotides upstream from coding exon 14 in the MSH2 gene. This variant has been identified in a proband whose Lynch syndrome-associated tumor demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC); however, this variant has also been identified in a proband who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated loss of MSH2/MSH6 expression by IHC (Ambry internal data). In addition, this variant has been identified in multiple probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH2/MSH6 expression by IHC (interlaboratory communication, Ambry internal data). This variant has been reported in a patient diagnosed with Muir-Torre syndrome whose personal history consisted of colorectal cancer at the age of 47 and prostate cancer, melanoma, and a sebaceous adenoma all at the age of 68. Tumor IHC analysis showed the absence of MSH2 and MSH6. The patient's family history of cancer consisted of a brother diagnosed with colorectal cancer at the age of 54, a father diagnosed with colorectal cancer at an unknown age, and a mother diagnosed with esophageal cancer at an unknown age (Mangold et al. Br J Dermatol. 2007 Jan;156(1):158-62). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Lynch syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 31, 2022

- -

Lynch syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 18, 2023

This variant causes a T to A nucleotide substitution at the -10 position of intron 13 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Lynch syndrome-associated cancers (communication with external laboratories; ClinVar SCV000580509.6, SCV000260343.7). This variant has also been reported in the literature in an individual affected with Muir-Torre syndrome with a family history of colorectal and esophageal cancer, and the proband's tumor showed lack of MSH2 and MSH6 protein expression (PMID: 17199584). This variant has been identified in 1/251118 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 17199584) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2023

This sequence change falls in intron 13 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 90927). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	1.5
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 2
DS_AL_spliceai		0.90		Position offset: 10

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608006; hg19: chr2-47705401;