chr2-47414420-TAA-T

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).

• 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: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: 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

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 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+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
-	-	4	not specified (4)
-	-	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;