NM_000251.3:c.2210+175G>A

Variant names:

• chr2-47476746-G-A
• rs4583514
• NM_000251.3:c.2210+175G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000251.3(MSH2):​c.2210+175G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 152,072 control chromosomes in the GnomAD database, including 21,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.50 (21097 hom., cov: 32)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.24
• Publications: 15 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: ClinGen, Orphanet, G2P
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

Specifications for MSH2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 2-47476746-G-A is Benign according to our data. Variant chr2-47476746-G-A is described in ClinVar as Benign. ClinVar VariationId is 676957.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.727 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.2210+175G>A		intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.2210+175G>A		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.2210+175G>A		intron	N/A	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.2210+175G>A		intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.2210+175G>A		intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.2261+175G>A		intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76094 AN: 151952 Hom.: 21067 Cov.: 32

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.521

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.501

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.501 AC: 76180 AN: 152072 Hom.: 21097 Cov.: 32 AF XY: 0.503 AC XY: 37360 AN XY: 74326

African (AFR) AF: 0.734 AC: 30436 AN: 41472

American (AMR) AF: 0.399 AC: 6095 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1150 AN: 3472

East Asian (EAS) AF: 0.665 AC: 3435 AN: 5166

South Asian (SAS) AF: 0.436 AC: 2101 AN: 4818

European-Finnish (FIN) AF: 0.501 AC: 5303 AN: 10580

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26109 AN: 67976

Other (OTH) AF: 0.455 AC: 959 AN: 2110

Alfa AF: 0.415 Hom.: 9553

Bravo AF: 0.503

Asia WGS AF: 0.555 AC: 1928 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.065
DANN	Benign	0.49
PhyloP100		-1.2
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: rs4583514; hg19: chr2-47703885;