2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAA

Variant names:

• chr2-47414420-TAAAAAA-T
• rs11309117
• NM_000251.3:c.942+24_942+29delAAAAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The ENST00000233146.7(MSH2):​c.942+3_942+8delAAAAAA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0139 in 1,032,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., cov: 0)
  • Exomes 𝑓: 0.015 (0 hom.)
• Consequence: MSH2 ENST00000233146.7 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts 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: Benign. The variant received -8 ACMG points.

• BP6: Variant 2-47414420-TAAAAAA-T is Benign according to our data. Variant chr2-47414420-TAAAAAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 695772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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+24_942+29delAAAAAA		intron	N/A	NP_000242.1
	MSH2	NM_001406674.1		c.942+24_942+29delAAAAAA		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.942+24_942+29delAAAAAA		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+8delAAAAAA		splice_region intron	N/A	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.942+3_942+8delAAAAAA		splice_region intron	N/A	ENSP00000384199.1
	MSH2	ENST00000918107.1		c.993+3_993+8delAAAAAA		splice_region intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.0000482 AC: 3 AN: 62234 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00158

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000621

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0148 AC: 14369 AN: 970486 Hom.: 0 AF XY: 0.0150 AC XY: 7230 AN XY: 481756

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

African (AFR) AF: 0.0159 AC: 339 AN: 21354

American (AMR) AF: 0.0199 AC: 364 AN: 18288

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 297 AN: 14542

East Asian (EAS) AF: 0.0289 AC: 670 AN: 23220

South Asian (SAS) AF: 0.0117 AC: 659 AN: 56560

European-Finnish (FIN) AF: 0.0324 AC: 681 AN: 21004

Middle Eastern (MID) AF: 0.0202 AC: 50 AN: 2474

European-Non Finnish (NFE) AF: 0.0138 AC: 10656 AN: 774964

Other (OTH) AF: 0.0171 AC: 653 AN: 38080

⚠️ 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: 0.0000482 AC: 3 AN: 62234 Hom.: 0 Cov.: 0 AF XY: 0.0000726 AC XY: 2 AN XY: 27562

⚠️ 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: 19366

American (AMR) AF: 0.00 AC: 0 AN: 4136

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: 1108

European-Finnish (FIN) AF: 0.00158 AC: 1 AN: 634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 102

European-Non Finnish (NFE) AF: 0.0000621 AC: 2 AN: 32198

Other (OTH) AF: 0.00 AC: 0 AN: 778

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Lynch syndrome 1 (2)
-	-	2	not provided (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Lynch syndrome (1)
-	-	1	MSH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=90/10	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;