5-80655314-T-C

Variant names:

• chr5-80655314-T-C
• rs408626
• NM_002439.5:c.237+350T>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.237+350T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 244,428 control chromosomes in the GnomAD database, including 27,625 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 0.47 (17054 hom., cov: 27)
  • Exomes 𝑓: 0.46 (10571 hom.)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.253
• Publications: 33 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, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• MSH3-related attenuated familial adenomatous polyposis

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

  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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002439.5. 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
	MSH3	NM_002439.5	MANE Select	c.237+350T>C		intron	N/A	NP_002430.3	P20585

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.237+350T>C		intron	N/A	ENSP00000265081.6	P20585
	MSH3	ENST00000658259.1		c.69+52T>C		intron	N/A	ENSP00000499617.1	A0A590UJW0
	MSH3	ENST00000667069.1		c.237+350T>C		intron	N/A	ENSP00000499502.1	A0A590UJN8

Frequencies

GnomAD3 genomes AF: 0.474 AC: 71154 AN: 150100 Hom.: 17046 Cov.: 27

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.534

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.421

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.446

GnomAD4 exome AF: 0.462 AC: 43554 AN: 94212 Hom.: 10571 Cov.: 0 AF XY: 0.458 AC XY: 20240 AN XY: 44186

African (AFR) AF: 0.538 AC: 2342 AN: 4350

American (AMR) AF: 0.514 AC: 1458 AN: 2836

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 2322 AN: 5502

East Asian (EAS) AF: 0.672 AC: 7773 AN: 11564

South Asian (SAS) AF: 0.306 AC: 400 AN: 1308

European-Finnish (FIN) AF: 0.410 AC: 378 AN: 922

Middle Eastern (MID) AF: 0.365 AC: 200 AN: 548

European-Non Finnish (NFE) AF: 0.425 AC: 25301 AN: 59582

Other (OTH) AF: 0.445 AC: 3380 AN: 7600

GnomAD4 genome AF: 0.474 AC: 71212 AN: 150216 Hom.: 17054 Cov.: 27 AF XY: 0.473 AC XY: 34651 AN XY: 73308

African (AFR) AF: 0.546 AC: 22041 AN: 40382

American (AMR) AF: 0.497 AC: 7524 AN: 15152

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 1460 AN: 3468

East Asian (EAS) AF: 0.615 AC: 3139 AN: 5100

South Asian (SAS) AF: 0.338 AC: 1615 AN: 4772

European-Finnish (FIN) AF: 0.447 AC: 4627 AN: 10354

Middle Eastern (MID) AF: 0.411 AC: 120 AN: 292

European-Non Finnish (NFE) AF: 0.432 AC: 29265 AN: 67694

Other (OTH) AF: 0.447 AC: 937 AN: 2096

Alfa AF: 0.456 Hom.: 2089

Bravo AF: 0.487

Asia WGS AF: 0.445 AC: 1543 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.8
DANN	Benign	0.67
PhyloP100		0.25
PromoterAI		-0.0060	Neutral
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: rs408626; hg19: chr5-79951133; COSMIC: COSV54147333; COSMIC: COSV54147333;