NM_000251.3:c.2635-11A>G

Variant names:

• chr2-47482768-A-G
• rs201291595
• NM_000251.3:c.2635-11A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000251.3(MSH2):​c.2635-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,604,426 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Scores: Splicing: ADA: 0.00002572
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.959
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-47482768-A-G is Benign according to our data. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815. Variant chr2-47482768-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 491815.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2635-11A>G		intron_variant	Intron 15 of 15	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2635-11A>G		intron_variant	Intron 15 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152270 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 250058 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.0000531

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 154 AN: 1452038 Hom.: 0 Cov.: 29 AF XY: 0.0000857 AC XY: 62 AN XY: 723044

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.000138 AC: 152 AN: 1103580

Other (OTH) AF: 0.0000333 AC: 2 AN: 60052

GnomAD4 genome AF: 0.0000262 AC: 4 AN: 152388 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74522

African (AFR) AF: 0.00 AC: 0 AN: 41600

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Sep 18, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 04, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1

Oct 01, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:1

Dec 16, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.56
DANN	Benign	0.66
PhyloP100		-0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs201291595; hg19: chr2-47709907;