NM_000251.3:c.1387-4511G>C

Variant names:

• chr2-47458520-G-C
• rs6724876
• NM_000251.3:c.1387-4511G>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.1387-4511G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 150,804 control chromosomes in the GnomAD database, including 24,424 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 0.54 (24424 hom., cov: 30)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.393
• Publications: 3 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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.787 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.1387-4511G>C		intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1387-4511G>C		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.1387-4511G>C		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.1387-4511G>C		intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1387-4511G>C		intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1438-4511G>C		intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.544 AC: 81997 AN: 150688 Hom.: 24379 Cov.: 30

Gnomad AFR AF: 0.794

Gnomad AMI AF: 0.538

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.544 AC: 82097 AN: 150804 Hom.: 24424 Cov.: 30 AF XY: 0.545 AC XY: 40070 AN XY: 73518

African (AFR) AF: 0.794 AC: 32691 AN: 41148

American (AMR) AF: 0.425 AC: 6451 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1318 AN: 3458

East Asian (EAS) AF: 0.662 AC: 3394 AN: 5130

South Asian (SAS) AF: 0.476 AC: 2285 AN: 4796

European-Finnish (FIN) AF: 0.532 AC: 5347 AN: 10042

Middle Eastern (MID) AF: 0.421 AC: 123 AN: 292

European-Non Finnish (NFE) AF: 0.427 AC: 28959 AN: 67752

Other (OTH) AF: 0.499 AC: 1043 AN: 2090

Alfa AF: 0.488 Hom.: 2318

Bravo AF: 0.546

Asia WGS AF: 0.577 AC: 2008 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.90
DANN	Benign	0.33
PhyloP100		-0.39
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: rs6724876; hg19: chr2-47685659;