chr2-47445430-G-A

Variant names:

• chr2-47445430-G-A
• rs1981929
• NM_000251.3:c.1277-118G>A

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.1277-118G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 721,528 control chromosomes in the GnomAD database, including 162,971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40716 hom., cov: 32)
  • Exomes 𝑓: 0.65 (122255 hom.)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.0930
• Publications: 22 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=-0.89).
• BP6: Variant 2-47445430-G-A is Benign according to our data. Variant chr2-47445430-G-A is described in ClinVar as Benign. ClinVar VariationId is 90599.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

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.1277-118G>A		intron	N/A	NP_000242.1
	MSH2	NM_001406674.1		c.1277-118G>A		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.1277-118G>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.1277-118G>A		intron	N/A	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.1277-118G>A		intron	N/A	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.1277-118G>A		intron	N/A	ENSP00000495455.1

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109272 AN: 152016 Hom.: 40656 Cov.: 32

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.642

Gnomad AMR AF: 0.730

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.854

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.708

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.691

GnomAD4 exome AF: 0.649 AC: 369473 AN: 569392 Hom.: 122255 AF XY: 0.648 AC XY: 197999 AN XY: 305614

African (AFR) AF: 0.907 AC: 13694 AN: 15092

American (AMR) AF: 0.787 AC: 23070 AN: 29306

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 11126 AN: 18886

East Asian (EAS) AF: 0.810 AC: 25808 AN: 31880

South Asian (SAS) AF: 0.705 AC: 40944 AN: 58038

European-Finnish (FIN) AF: 0.711 AC: 25194 AN: 35412

Middle Eastern (MID) AF: 0.636 AC: 1889 AN: 2970

European-Non Finnish (NFE) AF: 0.597 AC: 207323 AN: 347114

Other (OTH) AF: 0.665 AC: 20425 AN: 30694

GnomAD4 genome AF: 0.719 AC: 109394 AN: 152136 Hom.: 40716 Cov.: 32 AF XY: 0.723 AC XY: 53767 AN XY: 74366

African (AFR) AF: 0.907 AC: 37696 AN: 41542

American (AMR) AF: 0.731 AC: 11156 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 2004 AN: 3466

East Asian (EAS) AF: 0.853 AC: 4420 AN: 5182

South Asian (SAS) AF: 0.705 AC: 3403 AN: 4830

European-Finnish (FIN) AF: 0.708 AC: 7483 AN: 10568

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.603 AC: 41009 AN: 67964

Other (OTH) AF: 0.691 AC: 1457 AN: 2110

Alfa AF: 0.610 Hom.: 47336

Bravo AF: 0.730

Asia WGS AF: 0.796 AC: 2761 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

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

Significance: Benign

Review Status: no assertion criteria provided

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

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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%

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.62
DANN	Benign	0.37
PhyloP100		0.093
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: rs1981929; hg19: chr2-47672569;