rs17218439

Variant names:

• chr2-47474963-G-A
• rs17218439
• NM_000251.3:c.1760-62G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47474963-G-A
• chr2-47474963-G-C
• chr2-47474963-G-T

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: 0.684
• 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: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -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 VariationId is 90775.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 72 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.1760-62G>A		intron	N/A	NP_000242.1
	MSH2	NM_001406674.1		c.1760-62G>A		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.1760-62G>A		intron	N/A	NP_001393560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1760-62G>A		intron	N/A	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.1760-62G>A		intron	N/A	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.1760-62G>A		intron	N/A	ENSP00000495455.1

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

African (AFR) AF: 0.0140 AC: 425 AN: 30258

American (AMR) AF: 0.0124 AC: 503 AN: 40492

Ashkenazi Jewish (ASJ) AF: 0.00821 AC: 206 AN: 25088

East Asian (EAS) AF: 0.000237 AC: 9 AN: 37980

South Asian (SAS) AF: 0.00600 AC: 483 AN: 80502

European-Finnish (FIN) AF: 0.0521 AC: 2565 AN: 49202

Middle Eastern (MID) AF: 0.00641 AC: 35 AN: 5456

European-Non Finnish (NFE) AF: 0.0342 AC: 33941 AN: 993054

Other (OTH) AF: 0.0268 AC: 1487 AN: 55432

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

African (AFR) AF: 0.0135 AC: 561 AN: 41542

American (AMR) AF: 0.0163 AC: 250 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4822

European-Finnish (FIN) AF: 0.0565 AC: 597 AN: 10570

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0354 AC: 2408 AN: 68018

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0262 Hom.: 18

Bravo AF: 0.0220

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

Lynch syndrome 1 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lynch syndrome Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1%

Hereditary cancer-predisposing syndrome Benign:1

Feb 04, 2016

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.53
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism

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