chr5-80782762-G-C

Variant names:

• chr5-80782762-G-C
• rs33008
• NM_002439.5:c.2435+3926G>C

Variant summary

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

The NM_002439.5(MSH3):​c.2435+3926G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,000 control chromosomes in the GnomAD database, including 4,357 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 (4357 hom., cov: 32)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.20
• Publications: 13 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=-0.71).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.2435+3926G>C		intron_variant	Intron 17 of 23	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.2435+3926G>C		intron_variant	Intron 17 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.2267+3926G>C		intron_variant	Intron 17 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1	c.2240+3926G>C		intron_variant	Intron 15 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.2435+3926G>C		intron_variant	Intron 17 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35376 AN: 151882 Hom.: 4357 Cov.: 32

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.233 AC: 35384 AN: 152000 Hom.: 4357 Cov.: 32 AF XY: 0.230 AC XY: 17060 AN XY: 74294

African (AFR) AF: 0.157 AC: 6503 AN: 41442

American (AMR) AF: 0.200 AC: 3059 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 807 AN: 3468

East Asian (EAS) AF: 0.255 AC: 1322 AN: 5178

South Asian (SAS) AF: 0.169 AC: 813 AN: 4812

European-Finnish (FIN) AF: 0.275 AC: 2904 AN: 10566

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.282 AC: 19185 AN: 67946

Other (OTH) AF: 0.249 AC: 525 AN: 2112

Alfa AF: 0.127 Hom.: 211

Bravo AF: 0.227

Asia WGS AF: 0.191 AC: 662 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.53
PhyloP100		2.2
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: rs33008; hg19: chr5-80078581; COSMIC: COSV54147861;