NM_000251.3:c.942+26_942+29delAAAA

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 NM_000251.3(MSH2):​c.942+26_942+29delAAAA variant causes a 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0071 (3 hom., cov: 0)
  • Exomes 𝑓: 0.089 (53 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• 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 -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 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. 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
	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
	MSH2	ENST00000406134.5	TSL:1	c.942+3_942+6delAAAA		splice_region intron	N/A	ENSP00000384199.1
	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 as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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;