17-43106514-G-C

Variant names:

• chr17-43106514-G-C
• rs80357084
• NM_007294.4:c.154C>G
• BRCA1 p.Leu52Val

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_Supporting

The NM_007294.4(BRCA1):c.154C>G (p.Leu52Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene BRCA1 is a tumor suppressor gene (CancerMine: 412 TSG, 22 oncogene, 49 driver citations). The gene BRCA1 is a cancer driver gene (CancerMine: 412 TSG, 22 oncogene, 49 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.L52F: Benign (ClinVar VariationId 37421, 3 stars); p.L52H: unknown significance (ClinVar VariationId 867282); p.L52I: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 91556); p.L52= (synonymous): Likely_benign (ClinVar VariationId 867894, 1 star); p.L52= (synonymous): unknown significance (ClinVar VariationId 867285); p.L52= (synonymous): unknown significance (ClinVar VariationId 867284); p.L52P: Uncertain_significance (ClinVar VariationId 409340, 2 stars); p.L52R: unknown significance (ClinVar VariationId 867283) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• Publications: 72 publications found

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 Gene-Disease associations (from GenCC):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA1 NM_007294.4	MANE Select	c.154C>G p.Leu52Val	missense	Exon 4 of 23	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407853.1		c.-35C>G	5_prime_UTR_premature_start_codon_gain	Exon 4 of 24	Prot: NP_001394782.1
	BRCA1 NM_001407879.1		c.-35C>G	5_prime_UTR_premature_start_codon_gain	Exon 4 of 23	Prot: NP_001394808.1

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.154C>Gp.Leu52Val

Exon rankExon 4 of 23

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407853.1

HGVSc / HGVSpc.-35C>G

Exon rankExon 4 of 24

5_prime_UTR_premature_start_codon_gain

Prot: NP_001394782.1

BRCA1 NM_001407879.1

HGVSc / HGVSpc.-35C>G

Exon rankExon 4 of 23

5_prime_UTR_premature_start_codon_gain

Prot: NP_001394808.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA1 ENST00000357654.9	TSL:1MANE Select	c.154C>G p.Leu52Val	missense	Exon 4 of 23	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.154C>G p.Leu52Val	missense	Exon 4 of 24	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.154C>G p.Leu52Val	missense	Exon 4 of 23	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.154C>Gp.Leu52Val

Exon rankExon 4 of 23

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.154C>Gp.Leu52Val

Exon rankExon 4 of 24

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.154C>Gp.Leu52Val

Exon rankExon 4 of 23

missense

Prot: ENSP00000419274.2UniProt: P38398-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:28
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary breast ovarian cancer syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.90	D
FuncVEP CTI	Pathogenic	0.72
GPN-Star LLR	N/A	-5.0
GPN-Star score	N/A	5.0
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.1	L
PhyloP100	Benign	1.3
popEVE	Benign	-4.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.87	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.69
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.037	D
Varity_R	N/A	0.63
VESM-3B	Benign	-8.0

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.12
Pangolin loss	Benign	0.12	Position offset: 19
SpliceAI score (max)	Benign	0.090	Details are displayed if max score is > 0.2

Showing 3 of 3 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 normal

3 no calibration

4 assays found for this variant.

Clinical calibration: 0 functionally abnormal (PS3), 1 functionally normal (BS3).

No calibration: 3 assays (score only).

Nucleotide level

BRCA1 SGE Normalized Scores

Meta-analysis of urn:mavedb:00000097-a-1, urn:mavedb:00000097-b-1, urn:mavedb:00000097-c-1, urn:mavedb:00000097-d-1, urn:mavedb:00000097-e-1 and 21 others

• Gene: BRCA1
• Assay type: Cell fitness
• Mechanism: Molecular function
• Model system: Immortalized human cells (Homo sapiens)
• Score: -0.105

Classified as

BS3 strongFunctionally normalFayer calibration: Functional

+4 more calibrations

BS3 strongFunctionally normalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Functional

BS3 strongFunctionally normalIGVF Coding Variant Focus Group -- Controls: All Variants: Functional

BS3 strongFunctionally normalRUO ExCALIBR calibration: BS3 Strong (-6)

BS3 strongFunctionally normalRUO ExCALIBR calibration (ClinVar 2018): BS3 Strong (-5)

Nucleotide level

Enrich2 nucleotide variant scores for BRCA1 Y2H

BRCA1 Y2H

• Gene: BRCA1
• Score: · p.Leu51Val (assay numbering)

No calibration data

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Nucleotide level

Enrich2 nucleotide variant scores for BRCA1 E3

BRCA1 E3

• Gene: BRCA1
• Score: 0.339 · p.Leu51Val (assay numbering)

No calibration data

This score is at approximately the 77th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Nucleotide level

BASE_ACMG quantities derived from the RING domain M2H functional assay

Functional Evaluation of BRCA1 RING Domain Missense Substitutions

• Gene: BRCA1 translation start through RING domain
• Score: -6.16 · p.Leu52Val (assay numbering)

No calibration data

This score is at approximately the 49th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs80357084;

hg19: chr17-41258531;

COSMIC: COSV58792036;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar