chr17-43092418-T-C

Variant names:

• chr17-43092418-T-C
• rs16941
• NM_007294.4:c.3113A>G
• BRCA1 p.Glu1038Gly

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-6 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -6 classification points (ACGS-UK Somatic Oncogenicity v2025). O4_SupportingB1_StrongB2_ModerateB3_Supporting

The NM_007294.4(BRCA1):c.3113A>G (p.Glu1038Gly) 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 0.334 (AC=538,509) in the gnomAD database across 1,613,370 control chromosomes, including 92,638 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.495. In-silico predictor (REVEL) classifies this variant as likely benign. 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.E1038?: Uncertain_significance (ClinVar VariationId 822926, 1 star); p.E1038A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 240786); p.E1038D: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 927721) The variant has been observed in cBioPortal in 16 samples across 6 studies and 13 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; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.30 (7403 hom., cov: 31)
  • Exomes 𝑓: 0.34 (85235 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:1 B:36 O:3
• Conservation: PhyloP100: -0.149
• Publications: 270 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: Likely_benign. The variant received -6 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=16 | studies=6 | cancer types=13 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.495 — exceeds 1% threshold (B1 applied)
	B2Does not fit gene mode of action		Exact variant classified as Likely Benign or Somatic Clinical Impact Tier IV in ClinVar — moderate benign evidence (B2); Exact variant classified as Likely Benign or Somatic Clinical Impact Tier IV in ClinVar — moderate benign evidence (B2)
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

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.3113A>G p.Glu1038Gly	missense	Exon 10 of 23	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407581.1		c.3113A>G p.Glu1038Gly	missense	Exon 10 of 24	Prot: NP_001394510.1 UniProt:
	BRCA1 NM_001407582.1		c.3113A>G p.Glu1038Gly	missense	Exon 10 of 24	Prot: NP_001394511.1 UniProt:

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.3113A>Gp.Glu1038Gly

Exon rankExon 10 of 23

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407581.1

HGVSc / HGVSpc.3113A>Gp.Glu1038Gly

Exon rankExon 10 of 24

missense

Prot: NP_001394510.1UniProt: A0A2R8Y7V5

BRCA1 NM_001407582.1

HGVSc / HGVSpc.3113A>Gp.Glu1038Gly

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.3113A>G p.Glu1038Gly	missense	Exon 10 of 23	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.3113A>G p.Glu1038Gly	missense	Exon 10 of 24	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.3113A>G p.Glu1038Gly	missense	Exon 10 of 23	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.3113A>Gp.Glu1038Gly

Exon rankExon 10 of 23

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.3113A>Gp.Glu1038Gly

Exon rankExon 10 of 24

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.3113A>Gp.Glu1038Gly

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: 0.300	AC:45583	Hom:7401	AN:151792	Cov:31
GnomAD2 exomes	AF: 0.348	AC:87427	Hom:	AN:251032	Cov:
GnomAD4 exome	AF: 0.337	AC:492920	Hom:85235	AN:1461460	Cov:50
GnomAD4 genome	AF: 0.300	AC:45589	Hom:7403	AN:151910	Cov:31
TOPMed (Bravo)	AF: 0.283	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.312	AC:179205	Hom:28965	AN:574086	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.283	AC:662	Hom:114	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.373	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.410	AC:123	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.279	AC:3629	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.405	AC:1408	Hom:	AN:3474	Cov:
Korea4K (4,157 Koreans)	AF: 0.312	AC:2257	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.349	AC:701	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.329	AC:40158	Hom:6699	AN:121944	Cov:
Turkish Variome	AF: 0.374	AC:2513	Hom:480	AN:6722	Cov:
UK10K	AF: 0.337	AC:2550	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.379	AC:3392	Hom:635	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.326 *	3628	11112	0.318 *	5608	17616
BipEx(Bipolar disorder (including schizoaffective))	0.325	9237	28420	0.322	9298	28844
Epi25(Epilepsy)	0.320	13429	41958	0.320	21420	66888
SCHEMA(Schizophrenia)	0.307	40584	132098	0.304	63856	210148

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
-	-	10	Breast-ovarian cancer, familial, susceptibility to, 1 (11)
-	-	9	not specified (10)
1	1	2	Familial cancer of breast (5)
-	-	4	Hereditary breast ovarian cancer syndrome (4)
-	-	4	not provided (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	BRCA1-related cancer predisposition (1)
-	-	1	Breast carcinoma (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	Benign	9.0
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.050	N
FuncVEP CTI	Benign	0.0033
GPN-Star LLR	N/A	-3.5
GPN-Star score	N/A	3.5
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.00023	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	98/2	polymorphism (auto)
MutationAssessor	Uncertain	2.3	M
PhyloP100	Benign	-0.15
popEVE	Benign	-3.6
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.23
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.028	D
Varity_R	N/A	0.13
VESM-3B	Benign	-3.3

Showing 27 of 27 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: rs16941;

hg19: chr17-41244435;

COSMIC: COSV58786412;

COSMIC: COSV58786412;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar