5-80805954-T-C

Variant names:

• chr5-80805954-T-C
• rs245397
• NM_002439.5:c.2656-7630T>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.2656-7630T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.846 in 152,160 control chromosomes in the GnomAD database, including 54,567 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 0.85 (54567 hom., cov: 31)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.592
• Publications: 9 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=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	NM_002439.5	MANE Select	c.2656-7630T>C		intron	N/A	NP_002430.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.2656-7630T>C		intron	N/A	ENSP00000265081.6
	MSH3	ENST00000658259.1		c.2488-7630T>C		intron	N/A	ENSP00000499617.1
	MSH3	ENST00000667069.1		c.2461-7630T>C		intron	N/A	ENSP00000499502.1

Frequencies

GnomAD3 genomes AF: 0.846 AC: 128639 AN: 152042 Hom.: 54509 Cov.: 31

Gnomad AFR AF: 0.870

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.854

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.876

Gnomad FIN AF: 0.855

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.831

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

GnomAD4 genome AF: 0.846 AC: 128757 AN: 152160 Hom.: 54567 Cov.: 31 AF XY: 0.849 AC XY: 63146 AN XY: 74378

African (AFR) AF: 0.870 AC: 36105 AN: 41508

American (AMR) AF: 0.854 AC: 13049 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 2762 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5179 AN: 5186

South Asian (SAS) AF: 0.877 AC: 4217 AN: 4808

European-Finnish (FIN) AF: 0.855 AC: 9052 AN: 10586

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.818 AC: 55638 AN: 68004

Other (OTH) AF: 0.833 AC: 1757 AN: 2108

Alfa AF: 0.827 Hom.: 113881

Bravo AF: 0.848

Asia WGS AF: 0.929 AC: 3229 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.12
DANN	Benign	0.52
PhyloP100		-0.59
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: rs245397; hg19: chr5-80101773;