NM_002439.5:c.199_207dupCCAGCTCCC

Variant names:

• chr5-80654922-G-GCCCCCAGCT
• rs3045983
• NM_002439.5:c.199_207dupCCAGCTCCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_002439.5(MSH3):​c.199_207dupCCAGCTCCC​(p.Pro67_Pro69dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A70A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.000017 (1 hom.)
• Consequence: MSH3 NM_002439.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0550
• Publications: 10 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]

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]

DHFR Gene-Disease associations (from GenCC):

• constitutional megaloblastic anemia with severe neurologic disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_002439.5.

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.199_207dupCCAGCTCCC	p.Pro67_Pro69dup	conservative_inframe_insertion	Exon 1 of 24	NP_002430.3
	DHFR	NM_000791.4	MANE Select	c.-442_-434dupAGCTGGGGG		5_prime_UTR	Exon 1 of 6	NP_000782.1
	DHFR	NR_110936.2		n.53_61dupAGCTGGGGG		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.199_207dupCCAGCTCCC	p.Pro67_Pro69dup	conservative_inframe_insertion	Exon 1 of 24	ENSP00000265081.6
	MSH3	ENST00000667069.1		c.199_207dupCCAGCTCCC	p.Pro67_Pro69dup	conservative_inframe_insertion	Exon 1 of 22	ENSP00000499502.1
	MSH3	ENST00000670357.1		n.199_207dupCCAGCTCCC		non_coding_transcript_exon	Exon 1 of 25	ENSP00000499791.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD2 exomes AF: 0.0000237 AC: 3 AN: 126454 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000167 AC: 23 AN: 1380954 Hom.: 1 Cov.: 16 AF XY: 0.0000132 AC XY: 9 AN XY: 683602

African (AFR) AF: 0.00 AC: 0 AN: 29094

American (AMR) AF: 0.000134 AC: 4 AN: 29760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23634

East Asian (EAS) AF: 0.00 AC: 0 AN: 33142

South Asian (SAS) AF: 0.0000255 AC: 2 AN: 78392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47962

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5474

European-Non Finnish (NFE) AF: 0.0000121 AC: 13 AN: 1076462

Other (OTH) AF: 0.0000526 AC: 3 AN: 57034

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 557

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Endometrial carcinoma;C4310719:Familial adenomatous polyposis 4 Uncertain:1

Feb 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.055
Mutation Taster		=83/17	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3045983; hg19: chr5-79950741;