chr2-47448192-G-C

Variant names:

• chr2-47448192-G-C
• rs3771275
• NM_000251.3:c.1386+2535G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000251.3(MSH2):​c.1386+2535G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 152,056 control chromosomes in the GnomAD database, including 23,481 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (23481 hom., cov: 32)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.883
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 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.1386+2535G>C		intron	N/A	NP_000242.1
	MSH2	NM_001406674.1		c.1386+2535G>C		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.1386+2535G>C		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.1386+2535G>C		intron	N/A	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.1386+2535G>C		intron	N/A	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.1386+2535G>C		intron	N/A	ENSP00000495455.1

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80229 AN: 151938 Hom.: 23436 Cov.: 32

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.488

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.528 AC: 80333 AN: 152056 Hom.: 23481 Cov.: 32 AF XY: 0.531 AC XY: 39448 AN XY: 74326

African (AFR) AF: 0.783 AC: 32467 AN: 41486

American (AMR) AF: 0.418 AC: 6385 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1288 AN: 3472

East Asian (EAS) AF: 0.676 AC: 3501 AN: 5182

South Asian (SAS) AF: 0.467 AC: 2254 AN: 4828

European-Finnish (FIN) AF: 0.530 AC: 5587 AN: 10542

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27214 AN: 67962

Other (OTH) AF: 0.488 AC: 1028 AN: 2108

Alfa AF: 0.482 Hom.: 2372

Bravo AF: 0.529

Asia WGS AF: 0.577 AC: 2008 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.63
DANN	Benign	0.25
PhyloP100		-0.88
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: rs3771275; hg19: chr2-47675331;