Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_007294.4(BRCA1):c.5073A>G (p.Thr1691=)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA003191

55374 (ClinVar)

Gene: BRCA1

Condition: BRCA1-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 90a8be26-130c-452a-9af7-49f94663218a

Approved on: 2024-06-12

Published on: 2024-06-11

HGVS expressions

NM_007294.4:c.5073A>G

NM_007294.4(BRCA1):c.5073A>G (p.Thr1691=)

NC_000017.11:g.43067609T>C

CM000679.2:g.43067609T>C

NC_000017.10:g.41219626T>C

CM000679.1:g.41219626T>C

NC_000017.9:g.38473152T>C

NG_005905.2:g.150375A>G

ENST00000461574.2:c.5070A>G

ENST00000470026.6:c.5073A>G

ENST00000473961.6:c.4947A>G

ENST00000476777.6:c.5067A>G

ENST00000477152.6:c.4995A>G

ENST00000478531.6:c.1761A>G

ENST00000489037.2:c.4995A>G

ENST00000493919.6:c.1623A>G

ENST00000494123.6:c.5073A>G

ENST00000497488.2:c.4185A>G

ENST00000618469.2:c.5073A>G

ENST00000634433.2:c.4950A>G

ENST00000644379.2:c.5139A>G

ENST00000644555.2:c.1623A>G

ENST00000652672.2:c.4932A>G

ENST00000484087.6:c.1635A>G

ENST00000357654.9:c.5073A>G

ENST00000471181.7:c.5136A>G

ENST00000644379.1:c.1460A>G

ENST00000352993.7:c.1647A>G

ENST00000357654.7:c.5073A>G

ENST00000461221.5:c.*4856A>G

ENST00000468300.5:c.1761A>G

ENST00000471181.6:c.5136A>G

ENST00000472490.1:n.226A>G

ENST00000478531.5:c.1761A>G

ENST00000484087.5:c.1386A>G

ENST00000491747.6:c.1761A>G

ENST00000493795.5:c.4932A>G

ENST00000493919.5:c.1623A>G

ENST00000586385.5:c.5-3658A>G

ENST00000591534.5:c.546A>G

ENST00000591849.5:c.-98-17419A>G

NM_007294.3:c.5073A>G

NM_007297.3:c.4932A>G

NM_007298.3:c.1761A>G

NM_007299.3:c.1761A>G

NM_007300.3:c.5136A>G

NR_027676.1:n.5209A>G

NM_007297.4:c.4932A>G

NM_007299.4:c.1761A>G

NM_007300.4:c.5136A>G

NR_027676.2:n.5250A>G

Uncertain Significance

PP3 PM2_Supporting

BS3 PS3

Evidence Links 0

Expert Panel

ENIGMA BRCA1 and BRCA2 VCEP

Criteria Specification Information

Criteria Specification: ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ENIGMA BRCA1 and BRCA2 VCEP

The c.5073A>G variant in BRCA1 is a synonymous variant (p.Thr1691=). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 silent variant has a SpliceAI predictor score of 0.71, predicting an impact on splicing (score threshold >0.20) (PP3 met). Although this variant was reported by one calibrated study to exhibit protein function similar to benign control variants, other silent variants at the same position (c.5073A>C/T) were reported to affect function similar to pathogenic control variants in the same assay (PMID: 30209399). Additionally, these three variants have the same predicted effect on splicing and a splicing impact was observed for variant c.5073A>G (Ambry personal communication) (BS3 not applied due to conflicting evidence). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3).

PP3

This BRCA1 silent variant has a SpliceAI predictor score of 0.71, predicting an impact on splicing (score threshold >0.20) (PP3 met).

PM2_Supporting

This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met).

BS3

Although this variant was reported by one calibrated study to exhibit protein function similar to benign control variants, other silent variants at the same position (c.5073A>C/T) were reported to affect function similar to pathogenic control variants in the same assay (PMID: 30209399). Additionally, these three variants have the same predicted effect on splicing and a splicing impact was observed for variant c.5073A>G (Ambry personal communication) (BS3 not applied due to conflicting evidence).

PS3

Curation History

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