17-43106477-C-T

Variant names:

• chr17-43106477-C-T
• rs55851803
• NM_007294.4:c.191G>A
• BRCA1 p.Cys64Tyr

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 22 classification points (ACMG Germline Pathogenicity v2019). PVS1PS3PM2PP5_Very_Strong

The NM_001407853.1(BRCA1):c.2+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. Note: NM_001407853.1 is not a MANE Select or MANE Plus Clinical transcript for BRCA1; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.00000138 (AC=2) in the gnomAD database across 1,449,660 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000907. 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: "SCV000075654: Experimental studies have shown that this missense change affects BRCA1 function (PMID:7894491, 8944023, 11326114, 19287957, 24516540)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.C64G: Pathogenic (ClinVar VariationId 17660, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.C64= (synonymous): unknown significance (ClinVar VariationId 867931); p.C64F: unknown significance (ClinVar VariationId 867930) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_001407853.1 splice_donor, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:29
• Conservation: PhyloP100: 4.11
• Publications: 59 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 22 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Splice site frameshift, NMD predicted, LoF disease mechanism — very strong (PVS1); Splice donor variant predicted to cause a frameshift, triggering NMD. Loss of function is a known disease mechanism for this gene.
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000075654: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 7894491, 8944023, 11326114, 19287957, 24516540).; SCV000918679: Several publications report experimental evidence evaluating an impact on protein function (example, Findlay_2018). The most pronounced variant effect results in a loss of homology directed repair (HDR) activity.; SCV005374666: "Reported by one calibrated study to exhibit protein function similar to pathogenic control variants." PMID: 30209399; SCV003927164: Experimental studies have shown that this missense change abolishes E3 ubiquitin ligase activity (PMID: 11320250).; SCV000186951: "This alteration is located in the highly conserved 5' RING domain and has been shown to result in abolished ubiquitin protein ligase activity (Ruffner H et al.Proc Natl Acad Sci USA. 2001 Apr 24;98(9):5134-9)."; SCV000911053: Functional studies have reported that this variant impacts BRCA1 function in ubiquitin ligase, BARD1 binding, haploid cell proliferation and yeast colony size assays (PMID: 11320250, 12732733, 25823446, 27272900, 30209399).; SCV000292502: Published functional studies demonstrate a damaging effect: reduced or absent ubiquitin ligase activity, decreased BARD1 binding, decreased cell survival, and abnormal yeast colony size and spot formation (Ruffner 2001, Starita 2015, Thouvenot 2016, Findlay 2018); SCV000600273: Multiple functional studies have demonstrated that this variant has a damaging effect on BRCA1 protein function (PMID: 30209399 (2018), 27272900 (2016), 25823446 (2015), 23397983 (2014), 22034289 (2012), 15131401 (2004), 8944023 (1996)).; SCV004101417: Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000907 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (29/29 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001407853.1. 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.191G>A p.Cys64Tyr	missense	Exon 4 of 23	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407853.1		c.2+1G>A	splice_donorintron	Intron 4 of 23	Prot: NP_001394782.1
	BRCA1 NM_001407879.1		c.2+1G>A	splice_donorintron	Intron 4 of 22	Prot: NP_001394808.1

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.191G>Ap.Cys64Tyr

Exon rankExon 4 of 23

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407853.1

HGVSc / HGVSpc.2+1G>A

Exon rankIntron 4 of 23

splice_donorintron

Prot: NP_001394782.1

BRCA1 NM_001407879.1

HGVSc / HGVSpc.2+1G>A

Exon rankIntron 4 of 22

splice_donorintron

Prot: NP_001394808.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA1 ENST00000357654.9	TSL:1MANE Select	c.191G>A p.Cys64Tyr	missense	Exon 4 of 23	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.191G>A p.Cys64Tyr	missense	Exon 4 of 24	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.191G>A p.Cys64Tyr	missense	Exon 4 of 23	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.191G>Ap.Cys64Tyr

Exon rankExon 4 of 23

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.191G>Ap.Cys64Tyr

Exon rankExon 4 of 24

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.191G>Ap.Cys64Tyr

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 0.00000138	AC:2	Hom:0	AN:1449660	Cov:28
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00000482	AC:1	Hom:0	AN:207320	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.0000240	1	41692	0.00	0	66720
SCHEMA(Schizophrenia)	0.0000148	1	67778	0.00	0	132972

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (11)
8	-	-	not provided (8)
5	-	-	Hereditary breast ovarian cancer syndrome (5)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	BRCA1-related cancer predisposition (1)
1	-	-	Inherited prostate cancer (1)
1	-	-	Pancreatic cancer, susceptibility to, 4 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	35
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
FuncVEP CTI	Pathogenic	0.99
GPN-Star LLR	N/A	-8.1
GPN-Star score	N/A	8.1
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.3	H
PhyloP100	Uncertain	4.1
popEVE	Benign	-4.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.2	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Varity_R	N/A	0.98
VESM-3B	Benign	-12

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
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: -2.05

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: -2.04 · p.Cys63Tyr (assay numbering)

No calibration data

This score is at approximately the 4th 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: · p.Cys63Tyr (assay numbering)

No calibration data

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: 9.69 · p.Cys64Tyr (assay numbering)

No calibration data

This score is at approximately the 89th 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: rs55851803;

hg19: chr17-41258494;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar