chr17-43106478-A-C

Variant names:

• chr17-43106478-A-C
• rs80357064
• NM_007294.4:c.190T>G
• BRCA1 p.Cys64Gly

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 21 classification points (ACMG Germline Pathogenicity v2019). PVS1PS1PS3PM2_SupportingPP5_Strong

The NM_001407853.1(BRCA1):c.2T>G (p.Met1?) variant causes a start lost, splice region 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. This is a canonical splice-site variant (loss-of-function). The variant allele was found at a cumulative frequency of 0.00000187 (AC=3) in the gnomAD database across 1,602,342 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000301. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004823687: Functional studies have reported that the variant impacts BRCA1 function in homology-directed repair, ubiquitin ligase, haploid cell proliferation and BARD1 binding assays and rescue of DNA damage sensitivity in BRCA1-deficient cells (PMID:8944023, 10635334, 11320250, 16403807, 20103620, 23867111, 25823446, 30209399)." 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.C64R: Pathogenic (ClinVar VariationId 54394, 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 established as oncogenic in: CGI (Cancer Genome Interpreter).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_001407853.1 start_lost, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 U:2
• Conservation: PhyloP100: 4.88
• Publications: 102 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 21 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Start-lost with downstream start: ≥7 pathogenic between starts — very strong ; Start codon lost (exon 4 of 24); downstream rescue start codon present, but 96 pathogenic variants between start codons indicate significant functional impact.
	PS1Same amino acid change as known pathogenic		Different start-lost, ≥3-star ClinVar pathogenic — strong (PS1); ClinVar contains 7 P/LP entries with the start-lost variant at the same initiation codon (highest review level: 3 stars).
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV004823687: Functional studies have reported that the variant impacts BRCA1 function in homology-directed repair, ubiquitin ligase, haploid cell proliferation and BARD1 binding assays and rescue of DNA damage sensitivity in BRCA1-deficient cells (PMID: 8944023, 10635334, 11320250, 16403807, 20103620, 23867111, 25823446, 30209399).; SCV000075647: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20103620, 23161852). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 12915465, 26689913; internal data).; SCV000698899: Functional studies using HeLa cells confirmed this variant to be deleterious by using homology-directed recombination (HDR) and single-strand annealing (SSA) assays (Ransburgh_2010, Towler_2013).; SCV004847796: In vitro and in vivo functional studies support an impact on protein function (Findlay 2018, Wu 1996, Ruffner 2001, Yang 2003, Bouwman 2013, Towler 2013, Morris 2006, Lu 2015, Castilla 1994, Ransburgh 2010, Starita 2015, Maxwell 2017).; SCV000184711: Several independent DNA repair assays showed loss of function in p.C64G point mutants for BRCA1 ubiquitin ligase activity, homology directed recombination, functional complementation, and a high-throughput, genome editing, haploid cell survival assay (Scully R et al. Mol Cell, 1999 Dec;4:1093-9; Morris JR et al. Hum. Mol. Genet. 2006 Feb;15:599-606; Ransburgh DJ et al. Cancer Res. 2010 Feb;70:988-95; Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55; Lu C et al. Nat Commun 2015 Dec;6:10086; Starita LM et al. Genetics. 2015 Jun;200:413-22; Findlay GM et al. Nature, 2018 10;562:217-222).; SCV000905209: Functional studies have reported that the variant impacts BRCA1 function in homology-directed repair, ubiquitin ligase, haploid cell proliferation and BARD1 binding assays and rescue of DNA damage sensitivity in BRCA1-deficient cells (PMID: 8944023, 10635334, 11320250, 16403807, 20103620, 23867111, 25823446, 30209399).; SCV000210068: Published functional studies demonstrate a damaging effect: defective homologous recombination and single-strand annealing repair, impaired BARD1 binding, and abrogation of ubiquitin ligase activity (Wu et al., 1996; Brzovic et al., 2003; Ransburgh et al., 2010; Bouwman et al., 2013; Towler et al., 2013; Lu et al., 2015)
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000301 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (13/15 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.190T>G p.Cys64Gly	missense	Exon 4 of 23	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407853.1		c.2T>G p.Met1?	start_lostsplice_region	Exon 4 of 24	Prot: NP_001394782.1
	BRCA1 NM_001407879.1		c.2T>G p.Met1?	start_lostsplice_region	Exon 4 of 23	Prot: NP_001394808.1

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.190T>Gp.Cys64Gly

Exon rankExon 4 of 23

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407853.1

HGVSc / HGVSpc.2T>Gp.Met1?

Exon rankExon 4 of 24

start_lostsplice_region

Prot: NP_001394782.1

BRCA1 NM_001407879.1

HGVSc / HGVSpc.2T>Gp.Met1?

Exon rankExon 4 of 23

start_lostsplice_region

Prot: NP_001394808.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA1 ENST00000357654.9	TSL:1MANE Select	c.190T>G p.Cys64Gly	missense	Exon 4 of 23	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.190T>G p.Cys64Gly	missense	Exon 4 of 24	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.190T>G p.Cys64Gly	missense	Exon 4 of 23	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.190T>Gp.Cys64Gly

Exon rankExon 4 of 23

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.190T>Gp.Cys64Gly

Exon rankExon 4 of 24

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.190T>Gp.Cys64Gly

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152218	Cov:32
GnomAD2 exomes	AF: 0.0000120	AC:3	Hom:	AN:250804	Cov:
GnomAD4 exome	AF: 6.90e-7	AC:1	Hom:0	AN:1450124	Cov:28
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152218	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:54060	Cov:

Showing 6 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (7)
3	-	-	Hereditary breast ovarian cancer syndrome (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	43
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Benign	0.67
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-8.3
GPN-Star score	N/A	8.3
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.6	H
PhyloP100	Uncertain	4.9
popEVE	Benign	-4.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.5	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	0.011	D
Varity_R	N/A	0.99
VESM-3B	Benign	-13

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_DL_spliceai	Pathogenic	0.65	Position offset: -22
Pangolin (max)	Pathogenic	0.75
Pangolin gain	Pathogenic	0.56	Position offset: 0
Pangolin loss	Pathogenic	0.75	Position offset: -22
SpliceAI score (max)	Pathogenic	0.65	Details are displayed if max score is > 0.2
Splicevardb	N/A	3.0

Showing 6 of 6 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: -1.95

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: -1.35 · p.Cys63Gly (assay numbering)

No calibration data

This score is at approximately the 14th 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.Cys63Gly (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: 9.92 · p.Cys64Gly (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: rs80357064;

hg19: chr17-41258495;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar