2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAA

Variant names:

• chr2-47414420-TAAA-T
• rs11309117
• NM_000251.3:c.942+27_942+29delAAA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The ENST00000233146.7(MSH2):​c.942+3_942+5delAAA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.156 in 949,752 control chromosomes in the GnomAD database, including 472 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (57 hom., cov: 0)
  • Exomes 𝑓: 0.16 (472 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 ENST00000233146.7 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• 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-TAAA-T is Benign according to our data. Variant chr2-47414420-TAAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 439908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 472 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+27_942+29delAAA		intron	N/A	NP_000242.1
	MSH2	NM_001406674.1		c.942+27_942+29delAAA		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.942+27_942+29delAAA		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+5delAAA		splice_region intron	N/A	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.942+3_942+5delAAA		splice_region intron	N/A	ENSP00000384199.1
	MSH2	ENST00000918107.1		c.993+3_993+5delAAA		splice_region intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.0583 AC: 3632 AN: 62322 Hom.: 57 Cov.: 0

Gnomad AFR AF: 0.0796

Gnomad AMI AF: 0.0608

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0102

Gnomad EAS AF: 0.00245

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0833

Gnomad MID AF: 0.0200

Gnomad NFE AF: 0.0549

Gnomad OTH AF: 0.0398

GnomAD2 exomes AF: 0.136 AC: 7135 AN: 52420 AF XY: 0.129

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.0563

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.156 AC: 148191 AN: 949752 Hom.: 472 AF XY: 0.155 AC XY: 73276 AN XY: 471362

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

African (AFR) AF: 0.138 AC: 2872 AN: 20784

American (AMR) AF: 0.143 AC: 2526 AN: 17690

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 2064 AN: 14242

East Asian (EAS) AF: 0.167 AC: 3758 AN: 22500

South Asian (SAS) AF: 0.146 AC: 8014 AN: 54750

European-Finnish (FIN) AF: 0.155 AC: 3214 AN: 20768

Middle Eastern (MID) AF: 0.159 AC: 386 AN: 2434

European-Non Finnish (NFE) AF: 0.157 AC: 119391 AN: 759344

Other (OTH) AF: 0.160 AC: 5966 AN: 37240

⚠️ 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: 0.0583 AC: 3632 AN: 62324 Hom.: 57 Cov.: 0 AF XY: 0.0578 AC XY: 1594 AN XY: 27596

African (AFR) AF: 0.0796 AC: 1542 AN: 19372

American (AMR) AF: 0.0405 AC: 168 AN: 4148

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 18 AN: 1768

East Asian (EAS) AF: 0.00245 AC: 4 AN: 1634

South Asian (SAS) AF: 0.00998 AC: 11 AN: 1102

European-Finnish (FIN) AF: 0.0833 AC: 53 AN: 636

Middle Eastern (MID) AF: 0.0204 AC: 2 AN: 98

European-Non Finnish (NFE) AF: 0.0549 AC: 1772 AN: 32276

Other (OTH) AF: 0.0397 AC: 31 AN: 780

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
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=87/13	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; COSMIC: COSV51876708; COSMIC: COSV51876708;