5-80654708-G-GCTGCCATCCTTGCC

Variant names:

• chr5-80654708-G-GCTGCCATCCTTGCC
• NM_002439.5:c.-12_2dupCCTTGCCCTGCCAT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002439.5(MSH3):​c.-12_2dupCCTTGCCCTGCCAT​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH3 NM_002439.5 frameshift, start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.672

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]

DHFR (HGNC:2861): (dihydrofolate reductase) Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate chromosomes. Dihydrofolate reductase deficiency has been linked to megaloblastic anemia. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.-12_2dupCCTTGCCCTGCCAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 24	ENST00000265081.7	NP_002430.3
DHFR	NM_000791.4	c.-233_-220dupGGCAAGGATGGCAG		5_prime_UTR_variant	Exon 1 of 6	ENST00000439211.7	NP_000782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.-12_2dupCCTTGCCCTGCCAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 24	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000667069.1	c.-12_2dupCCTTGCCCTGCCAT	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 22			ENSP00000499502.1
DHFR	ENST00000439211.7	c.-233_-220dupGGCAAGGATGGCAG		5_prime_UTR_variant	Exon 1 of 6	1	NM_000791.4	ENSP00000396308.2
MSH3	ENST00000670357.1	n.-12_2dupCCTTGCCCTGCCAT		non_coding_transcript_exon_variant	Exon 1 of 25			ENSP00000499791.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-12_2dup14 variant spans from the 5' untranslated region (5’UTR) and into coding exon 1 of the MSH3 gene. This variant results from a duplication of 14 nucleotides from positions -12 to 2 in the MSH3 gene, but does not alter the methionine at the first translated codon. This nucleotide region is generally well conserved in available vertebrate species. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-79950527;