2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAA

Variant names:

• chr2-47414420-TA-T
• rs11309117
• NM_000251.3:c.942+29delA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_000251.3(MSH2):​c.942+29delA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.52 (7247 hom., cov: 0)
  • Exomes 𝑓: 0.19 (2857 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 2.32
• Publications: 4 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.

• BP6: Variant 2-47414420-TA-T is Benign according to our data. Variant chr2-47414420-TA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 374958.
• BS2: High Homozygotes in GnomAdExome4 at 2857 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.942+29delA		intron_variant	Intron 5 of 15	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.942+3delA		splice_region_variant, intron_variant	Intron 5 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.523 AC: 32386 AN: 61918 Hom.: 7242 Cov.: 0

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.567

GnomAD2 exomes AF: 0.0792 AC: 4150 AN: 52420 AF XY: 0.0737

Gnomad AFR exome AF: 0.0689

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.0620

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0627

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.186 AC: 174831 AN: 937556 Hom.: 2857 Cov.: 0 AF XY: 0.183 AC XY: 84884 AN XY: 463688

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.121 AC: 2489 AN: 20568

American (AMR) AF: 0.107 AC: 1776 AN: 16622

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 1865 AN: 13994

East Asian (EAS) AF: 0.130 AC: 2853 AN: 21890

South Asian (SAS) AF: 0.134 AC: 6972 AN: 51882

European-Finnish (FIN) AF: 0.115 AC: 2288 AN: 19934

Middle Eastern (MID) AF: 0.172 AC: 408 AN: 2376

European-Non Finnish (NFE) AF: 0.199 AC: 149819 AN: 753694

Other (OTH) AF: 0.174 AC: 6361 AN: 36596

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.523 AC: 32391 AN: 61922 Hom.: 7247 Cov.: 0 AF XY: 0.519 AC XY: 14222 AN XY: 27428

African (AFR) AF: 0.378 AC: 7206 AN: 19056

American (AMR) AF: 0.622 AC: 2565 AN: 4126

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 1069 AN: 1770

East Asian (EAS) AF: 0.605 AC: 991 AN: 1638

South Asian (SAS) AF: 0.543 AC: 601 AN: 1106

European-Finnish (FIN) AF: 0.593 AC: 375 AN: 632

Middle Eastern (MID) AF: 0.571 AC: 56 AN: 98

European-Non Finnish (NFE) AF: 0.585 AC: 18846 AN: 32220

Other (OTH) AF: 0.569 AC: 437 AN: 768

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Sep 16, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 1 Uncertain:1 Benign:1

Sep 01, 2015

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mismatch repair cancer syndrome 1 Uncertain:1

Jun 28, 2018

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Jun 11, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Sep 25, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs11309117; hg19: chr2-47641559; COSMIC: COSV99253990; COSMIC: COSV99253990;