2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAA

Variant names:

• chr2-47414420-TA-T
• rs11309117
• NM_000251.3:c.942+29delA

Variant summary

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

The ENST00000233146.7(MSH2):​c.942+3delA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.52 (7247 hom., cov: 0)
  • Exomes 𝑓: 0.19 (2857 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 ENST00000233146.7 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 2.32
• 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 2-47414420-TA-T is Benign according to our data. Variant chr2-47414420-TA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 374958.
• BS2: High Homozygotes in GnomAdExome4 at 2857 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+29delA		intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.942+29delA		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.942+29delA		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+3delA		splice_region intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.942+3delA		splice_region intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.993+3delA		splice_region intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.523 AC: 32386 AN: 61918 Hom.: 7242 Cov.: 0

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.567

GnomAD2 exomes AF: 0.0792 AC: 4150 AN: 52420 AF XY: 0.0737

Gnomad AFR exome AF: 0.0689

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.0620

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0627

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.186 AC: 174831 AN: 937556 Hom.: 2857 Cov.: 0 AF XY: 0.183 AC XY: 84884 AN XY: 463688

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

African (AFR) AF: 0.121 AC: 2489 AN: 20568

American (AMR) AF: 0.107 AC: 1776 AN: 16622

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 1865 AN: 13994

East Asian (EAS) AF: 0.130 AC: 2853 AN: 21890

South Asian (SAS) AF: 0.134 AC: 6972 AN: 51882

European-Finnish (FIN) AF: 0.115 AC: 2288 AN: 19934

Middle Eastern (MID) AF: 0.172 AC: 408 AN: 2376

European-Non Finnish (NFE) AF: 0.199 AC: 149819 AN: 753694

Other (OTH) AF: 0.174 AC: 6361 AN: 36596

⚠️ 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: 0.523 AC: 32391 AN: 61922 Hom.: 7247 Cov.: 0 AF XY: 0.519 AC XY: 14222 AN XY: 27428

African (AFR) AF: 0.378 AC: 7206 AN: 19056

American (AMR) AF: 0.622 AC: 2565 AN: 4126

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 1069 AN: 1770

East Asian (EAS) AF: 0.605 AC: 991 AN: 1638

South Asian (SAS) AF: 0.543 AC: 601 AN: 1106

European-Finnish (FIN) AF: 0.593 AC: 375 AN: 632

Middle Eastern (MID) AF: 0.571 AC: 56 AN: 98

European-Non Finnish (NFE) AF: 0.585 AC: 18846 AN: 32220

Other (OTH) AF: 0.569 AC: 437 AN: 768

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	1	1	Lynch syndrome 1 (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Mismatch repair cancer syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.3
Mutation Taster		=98/2	polymorphism (auto)

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: COSV99253990; COSMIC: COSV99253990;