2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAA

Variant names:

• chr2-47414420-TAAAAA-T
• rs11309117
• NM_000251.3:c.942+25_942+29delAAAAA

Variant summary

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

The ENST00000233146.7(MSH2):​c.942+3_942+7delAAAAA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0393 in 957,072 control chromosomes in the GnomAD database, including 10 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.039 (10 hom.)
  • Failed GnomAD Quality Control
• 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: 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-TAAAAA-T is Benign according to our data. Variant chr2-47414420-TAAAAA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252474.
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR 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+25_942+29delAAAAA		intron	N/A	NP_000242.1
	MSH2	NM_001406674.1		c.942+25_942+29delAAAAA		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.942+25_942+29delAAAAA		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+7delAAAAA		splice_region intron	N/A	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.942+3_942+7delAAAAA		splice_region intron	N/A	ENSP00000384199.1
	MSH2	ENST00000918107.1		c.993+3_993+7delAAAAA		splice_region intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 9 AN: 62234 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000248

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0292 AC: 1529 AN: 52420 AF XY: 0.0271

Gnomad AFR exome AF: 0.0333

Gnomad AMR exome AF: 0.0375

Gnomad ASJ exome AF: 0.0268

Gnomad EAS exome AF: 0.0314

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.0267

Gnomad OTH exome AF: 0.0295

GnomAD4 exome AF: 0.0393 AC: 37619 AN: 957072 Hom.: 10 AF XY: 0.0397 AC XY: 18838 AN XY: 474702

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

African (AFR) AF: 0.0400 AC: 839 AN: 20992

American (AMR) AF: 0.0482 AC: 854 AN: 17732

Ashkenazi Jewish (ASJ) AF: 0.0475 AC: 681 AN: 14350

East Asian (EAS) AF: 0.0617 AC: 1398 AN: 22642

South Asian (SAS) AF: 0.0372 AC: 2059 AN: 55326

European-Finnish (FIN) AF: 0.0651 AC: 1349 AN: 20710

Middle Eastern (MID) AF: 0.0496 AC: 121 AN: 2438

European-Non Finnish (NFE) AF: 0.0374 AC: 28614 AN: 765368

Other (OTH) AF: 0.0454 AC: 1704 AN: 37514

⚠️ 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: 0.000145 AC: 9 AN: 62236 Hom.: 0 Cov.: 0 AF XY: 0.000181 AC XY: 5 AN XY: 27570

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

African (AFR) AF: 0.00 AC: 0 AN: 19372

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1768

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

South Asian (SAS) AF: 0.00 AC: 0 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: 0.000248 AC: 8 AN: 32194

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000161101), which strongly suggests a high chance of mosaicism in these individuals.

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 1 (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)
-	-	1	Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=69/31	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;