2-47478262-T-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000251.3(MSH2):c.2211-10T>A variant causes a 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 intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.32

Publications

3 publications found

Variant links:

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]

MSH2 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
mismatch repair cancer syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MSH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 90927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3 link	c.2211-10T>A		intron_variant	Intron 13 of 15	ENST00000233146.7	NP_000242.1	P43246-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7 link	c.2211-10T>A		intron_variant	Intron 13 of 15	1	NM_000251.3	ENSP00000233146.2		P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251118

AF XY:

0.00000737

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461242

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726810

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111574

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Feb 15, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Dec 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Lynch syndrome 1

Pathogenic:1

Jan 31, 2022

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lynch syndrome

Pathogenic:1

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1

Apr 05, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 (internal data). 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: 90927). Studies have shown that this variant is associated with inconclusive levels of altered splicing (internal data). 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

(source)

DANN

Benign

0.82

PhyloP100

2.3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over