17-43106469-C-A

Variant names:

• chr17-43106469-C-A
• rs80357102
• NM_007294.4:c.199G>T
• BRCA1 p.Asp67Tyr

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACMG Germline Pathogenicity v2019). PM1PM2_SupportingPP3BP6_Very_Strong

The NM_007294.4(BRCA1):c.199G>T (p.Asp67Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000827 (AC=132) in the gnomAD database across 1,596,780 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000914. 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 Benign/Likely Benign (★★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D67A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 867325); p.D67= (synonymous): Benign (ClinVar VariationId 427246, 3 stars); p.D67E: Uncertain_significance (ClinVar VariationId 54439, 1 star); p.D67E: unknown significance (ClinVar VariationId 867327); p.D67G: Uncertain_significance (ClinVar VariationId 867326, 1 star); p.D67H: unknown significance (ClinVar VariationId 867324); p.D67N: Uncertain_significance (ClinVar VariationId 91572, 0 stars); p.D67V: Uncertain_significance (ClinVar VariationId 409307, 2 stars) 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: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:19
• Conservation: PhyloP100: 0.0330
• Publications: 18 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: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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: 18 pathogenic, 16 benign (OR vs. background: 5.6).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000914 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000118 by highest known P/LP ClinVar AF 0.000118) — PM2 supporting.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 3 star(s). ClinVar submissions strongly and reliably favor benignity (19/23 total B/LB).

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.199G>T p.Asp67Tyr	missense	Exon 4 of 23	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407581.1		c.199G>T p.Asp67Tyr	missense	Exon 4 of 24	Prot: NP_001394510.1 UniProt:
	BRCA1 NM_001407582.1		c.199G>T p.Asp67Tyr	missense	Exon 4 of 24	Prot: NP_001394511.1 UniProt:

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.199G>Tp.Asp67Tyr

Exon rankExon 4 of 23

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407581.1

HGVSc / HGVSpc.199G>Tp.Asp67Tyr

Exon rankExon 4 of 24

missense

Prot: NP_001394510.1UniProt: A0A2R8Y7V5

BRCA1 NM_001407582.1

HGVSc / HGVSpc.199G>Tp.Asp67Tyr

Exon rankExon 4 of 24

missense

Prot: NP_001394511.1UniProt: A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA1 ENST00000357654.9	TSL:1MANE Select	c.199G>T p.Asp67Tyr	missense	Exon 4 of 23	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.199G>T p.Asp67Tyr	missense	Exon 4 of 24	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.199G>T p.Asp67Tyr	missense	Exon 4 of 23	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.199G>Tp.Asp67Tyr

Exon rankExon 4 of 23

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.199G>Tp.Asp67Tyr

Exon rankExon 4 of 24

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.199G>Tp.Asp67Tyr

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: 0.0000591	AC:9	Hom:0	AN:152198	Cov:32
GnomAD2 exomes	AF: 0.0000719	AC:18	Hom:	AN:250382	Cov:
GnomAD4 exome	AF: 0.0000852	AC:123	Hom:0	AN:1444464	Cov:28
GnomAD4 genome	AF: 0.0000591	AC:9	Hom:0	AN:152316	Cov:32
TOPMed (Bravo)	AF: 0.0000378	AC:10	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000626	AC:25	Hom:0	AN:399530	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000154	AC:2	Hom:	AN:12986	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000707	2	28292	0.0000697	2	28694
Epi25(Epilepsy)	0.0000720	3	41654	0.000120	8	66684
SCHEMA(Schizophrenia)	0.0000354	4	112860	0.0000632	12	189848

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	2	4	Breast-ovarian cancer, familial, susceptibility to, 1 (6)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	1	1	Hereditary breast ovarian cancer syndrome (2)
-	-	2	not provided (2)
-	1	-	Breast and/or ovarian cancer (1)
-	-	1	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)
-	-	1	Malignant tumor of breast (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.60	D
FuncVEP CTI	Benign	0.0011
GPN-Star LLR	N/A	-3.9
GPN-Star score	N/A	3.9
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	-0.062	T
Mutation Taster	N/A	74/26	polymorphism
MutationAssessor	Benign	1.3	L
PhyloP100	Benign	0.033
popEVE	Benign	-4.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.022	D
Varity_R	N/A	0.29
VESM-3B	Benign	-8.5

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.10
Pangolin gain	Benign	0.10	Position offset: 9
SpliceAI score (max)	Benign	0.19	Details are displayed if max score is > 0.2
Splicevardb	N/A	0.0

Showing 4 of 4 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: -0.0810

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: 0.312 · p.Asp66Tyr (assay numbering)

No calibration data

This score is at approximately the 65th 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: -1.42 · p.Asp66Tyr (assay numbering)

No calibration data

This score is at approximately the 23th 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: -9.95 · p.Asp67Tyr (assay numbering)

No calibration data

This score is at approximately the 23th 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: rs80357102;

hg19: chr17-41258486;

COSMIC: COSV105897737;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar