17-43091783-C-T

Variant names:

• chr17-43091783-C-T
• rs28897686
• NM_007294.4:c.3748G>A
• BRCA1 p.Glu1250Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O4_Supporting

The NM_007294.4(BRCA1):c.3748G>A (p.Glu1250Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene BRCA1 is a tumor suppressor gene (CancerMine: 412 TSG, 22 oncogene, 49 driver citations). The gene BRCA1 is a cancer driver gene (CancerMine: 412 TSG, 22 oncogene, 49 driver citations). The variant allele was found at a cumulative frequency of 0.000306 (AC=494) in the gnomAD database across 1,614,032 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000371. 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.E1250A: Uncertain_significance (ClinVar VariationId 4842652, 1 star); p.E1250D: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 531374); p.E1250D: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 141786); p.E1250= (synonymous): Likely_benign (ClinVar VariationId 232493, 3 stars); p.E1250G: Uncertain_significance (ClinVar VariationId 2748795, 1 star) The variant has been observed in cBioPortal in 7 samples across 6 studies and 4 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). 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: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:33 O:1
• Conservation: PhyloP100: 0.505
• Publications: 17 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 ACGS-UK Somatic Oncogenicity v2025

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: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=7 | studies=6 | cancer types=4 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.

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>A p.Glu1250Lys	missense	Exon 10 of 23	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407581.1		c.3748G>A p.Glu1250Lys	missense	Exon 10 of 24	Prot: NP_001394510.1 UniProt:
	BRCA1 NM_001407582.1		c.3748G>A p.Glu1250Lys	missense	Exon 10 of 24	Prot: NP_001394511.1 UniProt:

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.3748G>Ap.Glu1250Lys

Exon rankExon 10 of 23

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407581.1

HGVSc / HGVSpc.3748G>Ap.Glu1250Lys

Exon rankExon 10 of 24

missense

Prot: NP_001394510.1UniProt: A0A2R8Y7V5

BRCA1 NM_001407582.1

HGVSc / HGVSpc.3748G>Ap.Glu1250Lys

Exon rankExon 10 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.3748G>A p.Glu1250Lys	missense	Exon 10 of 23	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.3748G>A p.Glu1250Lys	missense	Exon 10 of 24	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.3748G>A p.Glu1250Lys	missense	Exon 10 of 23	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.3748G>Ap.Glu1250Lys

Exon rankExon 10 of 23

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.3748G>Ap.Glu1250Lys

Exon rankExon 10 of 24

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.3748G>Ap.Glu1250Lys

Exon rankExon 10 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: 0.000158	AC:24	Hom:0	AN:152196	Cov:32
GnomAD2 exomes	AF: 0.000199	AC:50	Hom:	AN:251234	Cov:
GnomAD4 exome	AF: 0.000322	AC:470	Hom:0	AN:1461836	Cov:32
GnomAD4 genome	AF: 0.000158	AC:24	Hom:0	AN:152196	Cov:32
TOPMed (Bravo)	AF: 0.000155	AC:41	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000220	AC:104	Hom:0	AN:473654	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000308	AC:4	Hom:	AN:13006	Cov:
Korea4K (4,157 Koreans)	AF: 0.000138	AC:1	Hom:	AN:7234	Cov:
Turkish Variome	AF: 0.000177	AC:1	Hom:0	AN:5172	Cov:
UK10K	AF: 0.000132	AC:1	Hom:	AN:7562	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000990 *	11	11112	0.000681 *	12	17618
BipEx(Bipolar disorder (including schizoaffective))	0.000633	18	28420	0.000693	20	28844
Epi25(Epilepsy)	0.000167	7	41958	0.000164	11	66888
SCHEMA(Schizophrenia)	0.000292	35	119702	0.000298	56	188070

Showing 4 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
-	1	9	not specified (11)
-	-	8	Breast-ovarian cancer, familial, susceptibility to, 1 (8)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	not provided (3)
-	-	2	Breast and/or ovarian cancer (2)
-	-	1	BRCA1-related cancer predisposition (1)
-	-	1	Breast neoplasm (1)
-	-	1	Malignant tumor of breast (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.2
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.082	N
FuncVEP CTI	Benign	0.00013
GPN-Star LLR	N/A	-1.7
GPN-Star score	N/A	1.7
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.83	T
Mutation Taster	N/A	74/26	polymorphism
MutationAssessor	Benign	1.6	L
PhyloP100	Benign	0.51
popEVE	Benign	-3.6
PrimateAI	Benign	0.24	T
PromoterAI	N/A	-0.027	Neutral
PROVEAN	Benign	-0.71	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.0
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.048	D
Varity_R	N/A	0.054
VESM-3B	Benign	-2.6

Showing 31 of 31 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	1.0

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.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs28897686;

hg19: chr17-41243800;

COSMIC: COSV58788553;

COSMIC: COSV58788553;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar