2-47414420-TAAAAAAAAAAAA-T

Variant names:

• chr2-47414420-TAAAAAAAAAAAA-T
• rs11309117
• NM_000251.3:c.942+18_942+29delAAAAAAAAAAAA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The ENST00000233146.7(MSH2):​c.942+3_942+14delAAAAAAAAAAAA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000305 in 1,044,300 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: 𝑓 0.00051 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: MSH2 ENST00000233146.7 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.75
• 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: Benign. The variant received -12 ACMG points.

• BP6: Variant 2-47414420-TAAAAAAAAAAAA-T is Benign according to our data. Variant chr2-47414420-TAAAAAAAAAAAA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1692301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000514 (32/62240) while in subpopulation SAS AF = 0.0154 (17/1106). AF 95% confidence interval is 0.00979. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000233146.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.942+18_942+29delAAAAAAAAAAAA		intron	N/A	NP_000242.1
	MSH2	NM_001406674.1		c.942+18_942+29delAAAAAAAAAAAA		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.942+18_942+29delAAAAAAAAAAAA		intron	N/A	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.942+3_942+14delAAAAAAAAAAAA		splice_region intron	N/A	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.942+3_942+14delAAAAAAAAAAAA		splice_region intron	N/A	ENSP00000384199.1
	MSH2	ENST00000918107.1		c.993+3_993+14delAAAAAAAAAAAA		splice_region intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.000514 AC: 32 AN: 62238 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000242

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000217

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000291 AC: 286 AN: 982060 Hom.: 0 AF XY: 0.000359 AC XY: 175 AN XY: 488110

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

African (AFR) AF: 0.000880 AC: 19 AN: 21592

American (AMR) AF: 0.000589 AC: 11 AN: 18674

Ashkenazi Jewish (ASJ) AF: 0.00244 AC: 36 AN: 14756

East Asian (EAS) AF: 0.00 AC: 0 AN: 23648

South Asian (SAS) AF: 0.00228 AC: 131 AN: 57422

European-Finnish (FIN) AF: 0.0000466 AC: 1 AN: 21450

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

European-Non Finnish (NFE) AF: 0.0000932 AC: 73 AN: 783454

Other (OTH) AF: 0.000389 AC: 15 AN: 38558

⚠️ 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 AF: 0.000514 AC: 32 AN: 62240 Hom.: 0 Cov.: 0 AF XY: 0.000725 AC XY: 20 AN XY: 27572

African (AFR) AF: 0.000258 AC: 5 AN: 19372

American (AMR) AF: 0.000242 AC: 1 AN: 4140

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 2 AN: 1768

East Asian (EAS) AF: 0.00 AC: 0 AN: 1634

South Asian (SAS) AF: 0.0154 AC: 17 AN: 1106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 100

European-Non Finnish (NFE) AF: 0.000217 AC: 7 AN: 32196

Other (OTH) AF: 0.00 AC: 0 AN: 780

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=77/23	polymorphism

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;