rs17218439

chr2-47474963-G-Achr2-47474963-G-Cchr2-47474963-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000251.3(MSH2):c.1760-62G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 1,469,684 control chromosomes in the GnomAD database, including 790 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.026 (72 hom., cov: 32)
  • Exomes 𝑓: 0.030 (718 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.684

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-47474963-G-A is Benign according to our data. Variant chr2-47474963-G-A is described in ClinVar as [Benign]. Clinvar id is 90775.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47474963-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0259 (3948/152220) while in subpopulation NFE AF= 0.0354 (2408/68018). AF 95% confidence interval is 0.0342. There are 72 homozygotes in gnomad4. There are 1959 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 72 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1760-62G>A		intron_variant		ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1760-62G>A		intron_variant		1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3947 AN: 152102 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0354

Gnomad OTH AF: 0.0191

GnomAD4 exome AF: 0.0301 AC: 39654 AN: 1317464 Hom.: 718 AF XY: 0.0292 AC XY: 19276 AN XY: 659826

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.00821

Gnomad4 EAS exome AF: 0.000237

Gnomad4 SAS exome AF: 0.00600

Gnomad4 FIN exome AF: 0.0521

Gnomad4 NFE exome AF: 0.0342

Gnomad4 OTH exome AF: 0.0268

GnomAD4 genome AF: 0.0259 AC: 3948 AN: 152220 Hom.: 72 Cov.: 32 AF XY: 0.0263 AC XY: 1959 AN XY: 74402

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0565

Gnomad4 NFE AF: 0.0354

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0298 Hom.: 9

Bravo AF: 0.0220

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

research

Mayo Clinic Laboratories, Mayo Clinic

-

- -

Lynch syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Vantari Genetics

Feb 04, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	3.2
Dann	Benign	0.53

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: rs17218439; hg19: chr2-47702102; COSMIC: COSV104575323; COSMIC: COSV104575323;