L1854P — LYFE SCIENCES

Genetic Information

Gene & Transcript Details

Gene

BRCA1

Transcript

NM_007294.3 MANE Select

Total Exons

—

Reference Sequence

NC_000017.10

Alternative Transcripts

ID	Status	Details
NM_007294.4	MANE Select	7088 nt \| 114–5705
NM_007294.2	Alternative	7191 nt \| 201–5792
NM_007294.3	RefSeq Select	7224 nt \| 233–5824

Variant Details

HGVS Notation

NM_007294.3:c.5561T>C

Protein Change

L1854P

Location

Exon 23 (Exon 23 of )

5'Exon Structure3'

Functional Consequence

Loss of Function

Alternate Identifiers

—

Clinical & Population Data

Population Frequency

gnomAD

Global Frequency

0.0 in 100,000

Extremely Rare

ACMG Criteria Applied PM2

This variant is absent or extremely rare in population databases (PM2 criteria applies).

ClinVar

Open

Classification

Likely Pathogenic

2 publications

Publications List

PMID: 35918668

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1854 of the BRCA1 protein (p.Leu1854Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 35918668). ClinVar contains an entry for this variant (Variation ID: 55631). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 20516115, 30209399, 30765603). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

PMID: 30209399

Classification criteria: PM2_supporting, PS3, PP3

PMID: 10923033

PMID: 17305420

The p.L1854P variant (also known as c.5561T>C), located in coding exon 22 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5561. The leucine at codon 1854 is replaced by proline, an amino acid with similar properties. Protein functional assays have demonstrated that this alteration is non-functional (Findlay GM et al. Nature, 2018 10;562:217-222; Fernandes VC et al. J Biol Chem, 2019 04;294:5980-5992; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Adamovich AI et al. Am J Hum Genet 2022 Apr;109(4):618-630). This alteration was also detected in 1/1664 individuals diagnosed with breast and/or ovarian cancer (Zhang Y et al. BMC Cancer, 2022 Aug;22:842).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Clinical Statement

"This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen expert panel."

COSMIC Somatic Evidence

Open

COSMIC ID

Recurrence

0 occurrences

PM1 Criteria

Not Applied

COSMIC Database Preview

Accessing full COSMIC database details requires institutional login or subscription.

Functional Impact & Domains

Functional Domain

Hotspot Status

Not a hotspot

Domain Summary

This variant is not located in a mutational hotspot or critical domain.

Related Variants in This Domain

No evidence of other pathogenic variants at this position in gene BRCA1.

Functional Studies & Therapeutic Relevance

OncoKB JAX-CKB

Functional Summary

Error in OpenAI Consolidation. OncoKB: BRCA1L1854PBRCA1L1854PSomaticNCBI Gene:672|Show additional gene information Variant OverviewBRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.The BRCA1 L1854P mutation is likely oncogenic.Hide mutation effect description The BRCA1 L1854P mutation is located in the BRCT domain of the protein. In a study of 117 distinct BRCA1 missense variants identified in patients with a known family history of breast or ovarian cancer, the L1854P variant was demonstrated to have no folding defect, normal binding activity, normal binding specificity and compromised transcriptional activity (PMID: 20516115) JAX-CKB: No results found

Database Previews

OncoKB

JAX-CKB

Click on previews to view full database entries. External databases may require institutional access.

Computational Analysis

Pathogenicity Predictions

SpliceAI

Predictor Consensus

Mixed/VUS

PP3 Applied

REVEL Score

0.0

Threshold: ≥0.75 = PP3 applied

SpliceAI Scores

Window: ±500bp

Effect Type	Score	Position
- Acceptor Loss (AL)	0.0	93 bp
- Donor Loss (DL)	0.0	215 bp
+ Acceptor Gain (AG)	0.0	-167 bp
+ Donor Gain (DG)	0.0	-47 bp

High impact (≥0.5) Medium impact (0.2-0.49) Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria (VCEP Specific)

Filter Criteria:

PS3

PS3 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

PM2

PM2 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

PP5

PP5 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

BP4

BP4 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)