chr5-80746456-T-C

Variant names:

• chr5-80746456-T-C
• rs863221
• NM_002439.5:c.1763+1841T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002439.5(MSH3):​c.1763+1841T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85
• Publications: 11 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

ENSG00000248967 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.1763+1841T>C		intron_variant	Intron 12 of 23	ENST00000265081.7	NP_002430.3
LOC124901016		n.80746456T>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.1763+1841T>C		intron_variant	Intron 12 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.1595+1841T>C		intron_variant	Intron 12 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1	c.1569-15090T>C		intron_variant	Intron 10 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.1763+1841T>C		intron_variant	Intron 12 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 339472 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 194876

African (AFR) AF: 0.00 AC: 0 AN: 9250

American (AMR) AF: 0.00 AC: 0 AN: 31200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10876

East Asian (EAS) AF: 0.00 AC: 0 AN: 11934

South Asian (SAS) AF: 0.00 AC: 0 AN: 61816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1140

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 177224

Other (OTH) AF: 0.00 AC: 0 AN: 15210

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.94
DANN	Benign	0.77
PhyloP100		2.9

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: rs863221; hg19: chr5-80042275;