2-47414420-TAAAA-T

Variant names:

• chr2-47414420-TAAAA-T
• rs11309117
• NM_000251.3:c.942+26_942+29delAAAA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The ENST00000233146.7(MSH2):​c.942+3_942+6delAAAA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0838 in 1,004,160 control chromosomes in the GnomAD database, including 56 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0071 (3 hom., cov: 0)
  • Exomes 𝑓: 0.089 (53 hom.)
• Consequence: MSH2 ENST00000233146.7 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• 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: ClinGen, Orphanet, G2P
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

Specifications for MSH2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 2-47414420-TAAAA-T is Benign according to our data. Variant chr2-47414420-TAAAA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 336428.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00709 (441/62232) while in subpopulation AFR AF = 0.0207 (401/19374). AF 95% confidence interval is 0.019. There are 3 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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+26_942+29delAAAA		intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.942+26_942+29delAAAA		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.942+26_942+29delAAAA		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+6delAAAA		splice_region intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.942+3_942+6delAAAA		splice_region intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.993+3_993+6delAAAA		splice_region intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 442 AN: 62230 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00218

Gnomad ASJ AF: 0.00170

Gnomad EAS AF: 0.000612

Gnomad SAS AF: 0.00451

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00514

GnomAD2 exomes AF: 0.0847 AC: 4442 AN: 52420 AF XY: 0.0830

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0705

Gnomad EAS exome AF: 0.111

Gnomad FIN exome AF: 0.0348

Gnomad NFE exome AF: 0.0738

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0889 AC: 83751 AN: 941928 Hom.: 53 AF XY: 0.0903 AC XY: 42096 AN XY: 466340

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

African (AFR) AF: 0.0906 AC: 1879 AN: 20740

American (AMR) AF: 0.104 AC: 1761 AN: 16932

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 1324 AN: 14008

East Asian (EAS) AF: 0.120 AC: 2657 AN: 22086

South Asian (SAS) AF: 0.0957 AC: 5124 AN: 53522

European-Finnish (FIN) AF: 0.112 AC: 2298 AN: 20430

Middle Eastern (MID) AF: 0.102 AC: 244 AN: 2394

European-Non Finnish (NFE) AF: 0.0861 AC: 64982 AN: 754908

Other (OTH) AF: 0.0943 AC: 3482 AN: 36908

⚠️ 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: 0.00709 AC: 441 AN: 62232 Hom.: 3 Cov.: 0 AF XY: 0.00714 AC XY: 197 AN XY: 27576

African (AFR) AF: 0.0207 AC: 401 AN: 19374

American (AMR) AF: 0.00217 AC: 9 AN: 4140

Ashkenazi Jewish (ASJ) AF: 0.00170 AC: 3 AN: 1768

East Asian (EAS) AF: 0.000612 AC: 1 AN: 1634

South Asian (SAS) AF: 0.00453 AC: 5 AN: 1104

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: 0.000559 AC: 18 AN: 32188

Other (OTH) AF: 0.00513 AC: 4 AN: 780

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	1	Lynch syndrome (2)
-	-	1	Breast carcinoma (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=58/42	polymorphism

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;