chr2-47414420-TAAAAAAAAAAAAAAAAAAA-T

Variant names:

• chr2-47414420-TAAAAAAAAAAAAAAAAAAA-T
• rs11309117
• NM_000251.3:c.942+11_942+29delAAAAAAAAAAAAAAAAAAA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000251.3(MSH2):​c.942+11_942+29delAAAAAAAAAAAAAAAAAAA variant causes a intron change. The variant allele was found at a frequency of 0.00000305 in 982,182 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.75
• 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 -2 ACMG points.

• BP6: Variant 2-47414420-TAAAAAAAAAAAAAAAAAAA-T is Benign according to our data. Variant chr2-47414420-TAAAAAAAAAAAAAAAAAAA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3072692.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.942+11_942+29delAAAAAAAAAAAAAAAAAAA		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+3_942+21delAAAAAAAAAAAAAAAAAAA		splice_region_variant, intron_variant	Intron 5 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000305 AC: 3 AN: 982182 Hom.: 0 AF XY: 0.00000205 AC XY: 1 AN XY: 488170

African (AFR) AF: 0.00 AC: 0 AN: 21594

American (AMR) AF: 0.00 AC: 0 AN: 18678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14772

East Asian (EAS) AF: 0.000127 AC: 3 AN: 23652

South Asian (SAS) AF: 0.00 AC: 0 AN: 57452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21458

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2506

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 783510

Other (OTH) AF: 0.00 AC: 0 AN: 38560

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lynch syndrome Benign:1

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7

Splicing

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

Other links and lift over

dbSNP: rs11309117; hg19: chr2-47641559;