rs80357370

Variant names:

• chr17-43106529-A-C
• rs80357370
• NM_007294.4:c.139T>G
• BRCA1 p.Cys47Gly

Your query was ambiguous. Multiple possible variants found:

• chr17-43106529-A-C
• chr17-43106529-A-G
• chr17-43106529-A-T

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 16 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_StrongPP5_Moderate

The NM_007294.4(BRCA1):c.139T>G (p.Cys47Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000696 (AC=1) in the gnomAD database across 1,435,876 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000918. 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 Pathogenic/Likely Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000698860: Multiple independent functional studies have demonstrated that this variant results in loss of homology directed repair activity of BRCA1 in addition to a loss of E3 ubiquitin ligase activity as well as its ability to bind to the UbcH5a protein.". A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.C47F: Pathogenic/Likely_pathogenic (ClinVar VariationId 54247, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.C47= (synonymous): Likely_benign (ClinVar VariationId 427311, 3 stars); p.C47S: unknown significance (ClinVar VariationId 868217); p.C47W: unknown significance (ClinVar VariationId 865192) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.84
• Publications: 3 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 ACMG Germline Pathogenicity v2019

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: Pathogenic. The variant received 16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000698860: Multiple independent functional studies have demonstrated that this variant results in loss of homology directed repair activity of BRCA1 in addition to a loss of E3 ubiquitin ligase activity as well as its ability to bind to the UbcH5a protein.
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 22 pathogenic, 16 benign (OR vs. background: 6.8).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000918 — very rare for AD+AR gene (base 0.0001, raised to 0.000118 by highest known P/LP ClinVar AF 0.000118) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.C47F: Pathogenic/Likely_pathogenic (ClinVar VariationId 54247, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.C47= (synonymous): Likely_benign (ClinVar VariationId 427311, 3 stars); p.C47S: unknown significance (ClinVar VariationId 868217); p.C47W: unknown significance (ClinVar VariationId 865192)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 1-star pathogenic — moderate (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 1 star(s).

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.139T>G p.Cys47Gly	missense	Exon 4 of 23	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407692.1		c.-3T>G	5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	Prot: NP_001394621.1 UniProt:
	BRCA1 NM_001407694.1		c.-3T>G	5_prime_UTR_premature_start_codon_gain	Exon 5 of 24	Prot: NP_001394623.1 UniProt:

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.139T>Gp.Cys47Gly

Exon rankExon 4 of 23

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407692.1

HGVSc / HGVSpc.-3T>G

Exon rankExon 2 of 21

5_prime_UTR_premature_start_codon_gain

Prot: NP_001394621.1UniProt: A0A9Y1QQK3P38398-8

BRCA1 NM_001407694.1

HGVSc / HGVSpc.-3T>G

Exon rankExon 5 of 24

5_prime_UTR_premature_start_codon_gain

Prot: NP_001394623.1UniProt: A0A9Y1QQK3P38398-8

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA1 ENST00000357654.9	TSL:1MANE Select	c.139T>G p.Cys47Gly	missense	Exon 4 of 23	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.139T>G p.Cys47Gly	missense	Exon 4 of 24	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.139T>G p.Cys47Gly	missense	Exon 4 of 23	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.139T>Gp.Cys47Gly

Exon rankExon 4 of 23

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.139T>Gp.Cys47Gly

Exon rankExon 4 of 24

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.139T>Gp.Cys47Gly

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 6.96e-7	AC:1	Hom:0	AN:1435876	Cov:27
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:30748	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122582	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	28
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-7.8
GPN-Star score	N/A	7.8
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.2	H
PhyloP100	Uncertain	4.8
popEVE	Benign	-4.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.025	D
Varity_R	N/A	0.99
VESM-3B	Benign	-13

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2
Splicevardb	N/A	2.0

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 abnormal

3 no calibration

4 assays found for this variant.

Clinical calibration: 1 functionally abnormal (PS3), 0 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: -2.44

Classified as

PS3 strongFunctionally abnormalFayer calibration: Non-functional

+4 more calibrations

PS3 strongFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Non-functional

PS3 strongFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Non-functional

PS3 strongFunctionally abnormalRUO ExCALIBR calibration: PS3 Strong (7)

PS3 strongFunctionally abnormalRUO ExCALIBR calibration (ClinVar 2018): PS3 Strong (5)

Nucleotide level

Enrich2 nucleotide variant scores for BRCA1 Y2H

BRCA1 Y2H

• Gene: BRCA1
• Score: -0.999 · p.Cys46Gly (assay numbering)

No calibration data

This score is at approximately the 19th 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

Enrich2 nucleotide variant scores for BRCA1 E3

BRCA1 E3

• Gene: BRCA1
• Score: -1.62 · p.Cys46Gly (assay numbering)

No calibration data

This score is at approximately the 20th 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: 8.11 · p.Cys47Gly (assay numbering)

No calibration data

This score is at approximately the 86th 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: rs80357370;

hg19: chr17-41258546;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar