chr2-47471169-A-G

Variant names:

• chr2-47471169-A-G
• rs3764959
• NM_000251.3:c.1759+107A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000251.3(MSH2):​c.1759+107A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 680,402 control chromosomes in the GnomAD database, including 45,949 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (15525 hom., cov: 32)
  • Exomes 𝑓: 0.32 (30424 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0160
• Publications: 10 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=-0.85).
• BP6: Variant 2-47471169-A-G is Benign according to our data. Variant chr2-47471169-A-G is described in ClinVar as Benign. ClinVar VariationId is 439907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1759+107A>G		intron_variant	Intron 11 of 15	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1759+107A>G		intron_variant	Intron 11 of 15	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62877 AN: 151936 Hom.: 15497 Cov.: 32

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.371

GnomAD4 exome AF: 0.322 AC: 170205 AN: 528348 Hom.: 30424 AF XY: 0.318 AC XY: 90410 AN XY: 284408

African (AFR) AF: 0.671 AC: 9877 AN: 14722

American (AMR) AF: 0.310 AC: 9906 AN: 31988

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 4373 AN: 18752

East Asian (EAS) AF: 0.593 AC: 18014 AN: 30364

South Asian (SAS) AF: 0.320 AC: 19294 AN: 60262

European-Finnish (FIN) AF: 0.386 AC: 16991 AN: 43994

Middle Eastern (MID) AF: 0.246 AC: 574 AN: 2330

European-Non Finnish (NFE) AF: 0.274 AC: 81566 AN: 297718

Other (OTH) AF: 0.341 AC: 9610 AN: 28218

GnomAD4 genome AF: 0.414 AC: 62957 AN: 152054 Hom.: 15525 Cov.: 32 AF XY: 0.416 AC XY: 30941 AN XY: 74324

African (AFR) AF: 0.674 AC: 27917 AN: 41438

American (AMR) AF: 0.346 AC: 5282 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 787 AN: 3472

East Asian (EAS) AF: 0.640 AC: 3309 AN: 5174

South Asian (SAS) AF: 0.342 AC: 1650 AN: 4820

European-Finnish (FIN) AF: 0.388 AC: 4096 AN: 10570

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18854 AN: 67980

Other (OTH) AF: 0.370 AC: 781 AN: 2110

Alfa AF: 0.330 Hom.: 3363

Bravo AF: 0.421

Asia WGS AF: 0.496 AC: 1722 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 02, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.59
DANN	Benign	0.41
PhyloP100		-0.016
Mutation Taster		=100/0	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: rs3764959; hg19: chr2-47698308;