2-47414420-TAAAAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAA

Variant names:

• chr2-47414420-TAA-T
• rs11309117
• NM_000251.3:c.942+28_942+29delAA

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+4delAA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.179 in 965,430 control chromosomes in the GnomAD database, including 1,339 homozygotes. 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 0.16 (371 hom., cov: 0)
  • Exomes 𝑓: 0.18 (1339 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 ENST00000233146.7 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:12
• 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: 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-TAA-T is Benign according to our data. Variant chr2-47414420-TAA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 336427.
• BS2: High Homozygotes in GnomAdExome4 at 1339 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+28_942+29delAA		intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.942+28_942+29delAA		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.942+28_942+29delAA		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+4delAA		splice_region intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.942+3_942+4delAA		splice_region intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.993+3_993+4delAA		splice_region intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 9816 AN: 62568 Hom.: 372 Cov.: 0

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.265

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.162

GnomAD2 exomes AF: 0.0914 AC: 4790 AN: 52420 AF XY: 0.0872

Gnomad AFR exome AF: 0.0887

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.0905

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.0335

Gnomad NFE exome AF: 0.0841

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.179 AC: 173109 AN: 965430 Hom.: 1339 AF XY: 0.176 AC XY: 84578 AN XY: 479320

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

African (AFR) AF: 0.149 AC: 3097 AN: 20816

American (AMR) AF: 0.125 AC: 2250 AN: 18064

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 2206 AN: 14504

East Asian (EAS) AF: 0.177 AC: 4047 AN: 22808

South Asian (SAS) AF: 0.140 AC: 7857 AN: 56198

European-Finnish (FIN) AF: 0.149 AC: 3102 AN: 20820

Middle Eastern (MID) AF: 0.187 AC: 461 AN: 2460

European-Non Finnish (NFE) AF: 0.186 AC: 143460 AN: 771958

Other (OTH) AF: 0.175 AC: 6629 AN: 37802

⚠️ 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: 0.157 AC: 9812 AN: 62570 Hom.: 371 Cov.: 0 AF XY: 0.160 AC XY: 4436 AN XY: 27718

African (AFR) AF: 0.161 AC: 3117 AN: 19350

American (AMR) AF: 0.163 AC: 682 AN: 4176

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 343 AN: 1782

East Asian (EAS) AF: 0.215 AC: 357 AN: 1658

South Asian (SAS) AF: 0.251 AC: 282 AN: 1122

European-Finnish (FIN) AF: 0.200 AC: 127 AN: 636

Middle Eastern (MID) AF: 0.270 AC: 27 AN: 100

European-Non Finnish (NFE) AF: 0.142 AC: 4617 AN: 32436

Other (OTH) AF: 0.160 AC: 125 AN: 782

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	2	-	Lynch syndrome (2)
-	1	1	Lynch syndrome 1 (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	MSH2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7
Mutation Taster		=99/1	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;