2-47403013-C-T

Variant names:

• chr2-47403013-C-T
• rs17224094
• NM_000251.3:c.-179C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000251.3(MSH2):​c.-179C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 691,204 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: MSH2 NM_000251.3 upstream_gene
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.708

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-47403013-C-T is Benign according to our data. Variant chr2-47403013-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141069.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.-179C>T		upstream_gene_variant		ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.-179C>T		upstream_gene_variant		1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152244 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00237

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00166 AC: 896 AN: 538842 Hom.: 2 Cov.: 6 AF XY: 0.00161 AC XY: 463 AN XY: 287652

Gnomad4 AFR exome AF: 0.000526

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.00216

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000239

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00213

Gnomad4 OTH exome AF: 0.00231

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152362 Hom.: 1 Cov.: 33 AF XY: 0.00130 AC XY: 97 AN XY: 74504

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00237

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 1 Uncertain:1

Mar 03, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 27, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Jul 01, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs17224094; hg19: chr2-47630152;