chr17-43091783-C-A

Variant names:

• chr17-43091783-C-A
• rs28897686
• NM_007294.4:c.3748G>T
• BRCA1 p.Glu1250*

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_007294.4(BRCA1):c.3748G>T (p.Glu1250*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.00000274 (AC=4) in the gnomAD database across 1,461,836 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000084. In-silico predictor (BayesDel (noAF)) 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: "SCV000699068: functional study showed variant with ~10% of relative HDR activity in comparison to WT BRCA1 (Lu_2015).". This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Breast-ovarian cancer, familial, susceptibility to, 1 (brovca1); it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA1 NM_007294.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:29 O:1
• Conservation: PhyloP100: 0.505
• Publications: 67 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		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 10 of 23) at amino acid 1250 of 1863, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000699068: functional study showed variant with ~10% of relative HDR activity in comparison to WT BRCA1 (Lu_2015).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000084 — very rare for AD+AR gene (base 0.0001, raised to 0.000118 by highest known P/LP ClinVar AF 0.000118) — 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_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.3748G>T p.Glu1250*	stop_gained	Exon 10 of 23	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407581.1		c.3748G>T p.Glu1250*	stop_gained	Exon 10 of 24	Prot: NP_001394510.1 UniProt:
	BRCA1 NM_001407582.1		c.3748G>T p.Glu1250*	stop_gained	Exon 10 of 24	Prot: NP_001394511.1 UniProt:

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.3748G>Tp.Glu1250*

Exon rankExon 10 of 23

stop_gained

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407581.1

HGVSc / HGVSpc.3748G>Tp.Glu1250*

Exon rankExon 10 of 24

stop_gained

Prot: NP_001394510.1UniProt: A0A2R8Y7V5

BRCA1 NM_001407582.1

HGVSc / HGVSpc.3748G>Tp.Glu1250*

Exon rankExon 10 of 24

stop_gained

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.3748G>T p.Glu1250*	stop_gained	Exon 10 of 23	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.3748G>T p.Glu1250*	stop_gained	Exon 10 of 24	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.3748G>T p.Glu1250*	stop_gained	Exon 10 of 23	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.3748G>Tp.Glu1250*

Exon rankExon 10 of 23

stop_gained

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.3748G>Tp.Glu1250*

Exon rankExon 10 of 24

stop_gained

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.3748G>Tp.Glu1250*

Exon rankExon 10 of 23

stop_gained

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:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000796	AC:2	Hom:	AN:251234	Cov:
GnomAD4 exome	AF: 0.00000274	AC:4	Hom:0	AN:1461836	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000122	AC:58	Hom:0	AN:473654	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888

Showing 1 cohortAllele 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
12	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (12)
7	-	-	not provided (7)
5	-	-	Hereditary breast ovarian cancer syndrome (6)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	BRCA1-related cancer predisposition (1)
1	-	-	Familial cancer of breast (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Uncertain	0.98
Eigen	Uncertain	0.22
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.24	N
GPN-Star LLR	N/A	-2.5
GPN-Star score	N/A	2.5
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Benign	0.51
PromoterAI	N/A	-0.025	Neutral
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.0

Showing 15 of 15 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

Showing 2 of 2 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.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs28897686;

hg19: chr17-41243800;

COSMIC: COSV99066375;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar