rs16941

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-43092418-T-C
• chr17-43092418-T-G
• chr17-43092418-T-A

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BA1BP4BP6_Very_Strong

The NM_007294.4(BRCA1):c.3113A>G (p.Glu1038Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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) 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: 265 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: Benign. The variant received -17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar germline classification: Benign/Likely Benign, 3 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4947 — exceeds 5%% threshold (BA1 applied)

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	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.3113A>G	p.Glu1038Gly	missense	Exon 10 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.3113A>G	p.Glu1038Gly	missense	Exon 10 of 24	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.3113A>G	p.Glu1038Gly	missense	Exon 10 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.3113A>G	p.Glu1038Gly	missense	Exon 10 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.3113A>G	p.Glu1038Gly	missense	Exon 10 of 23	ENSP00000419274.2	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.

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