5-80669717-A-G

Variant names:

• chr5-80669717-A-G
• rs6151627
• NM_002439.5:c.580-380A>G

Variant summary

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

The NM_002439.5(MSH3):​c.580-380A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,126 control chromosomes in the GnomAD database, including 4,108 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 0.23 (4108 hom., cov: 32)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131
• Publications: 14 publications found

Genes affected

MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]

MSH3 Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• MSH3-related attenuated familial adenomatous polyposis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Lynch syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.580-380A>G		intron_variant	Intron 3 of 23	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.580-380A>G		intron_variant	Intron 3 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.412-380A>G		intron_variant	Intron 3 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1	c.580-380A>G		intron_variant	Intron 3 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.580-380A>G		intron_variant	Intron 3 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34515 AN: 152008 Hom.: 4107 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.241

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

GnomAD4 genome AF: 0.227 AC: 34521 AN: 152126 Hom.: 4108 Cov.: 32 AF XY: 0.224 AC XY: 16675 AN XY: 74370

African (AFR) AF: 0.157 AC: 6513 AN: 41506

American (AMR) AF: 0.197 AC: 3013 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 799 AN: 3468

East Asian (EAS) AF: 0.258 AC: 1332 AN: 5168

South Asian (SAS) AF: 0.155 AC: 750 AN: 4828

European-Finnish (FIN) AF: 0.268 AC: 2829 AN: 10554

Middle Eastern (MID) AF: 0.236 AC: 69 AN: 292

European-Non Finnish (NFE) AF: 0.272 AC: 18520 AN: 67992

Other (OTH) AF: 0.239 AC: 506 AN: 2116

Alfa AF: 0.251 Hom.: 2462

Bravo AF: 0.223

Asia WGS AF: 0.191 AC: 663 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.7
DANN	Benign	0.89
PhyloP100		0.13
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: rs6151627; hg19: chr5-79965536; COSMIC: COSV54147405;