NM_007294.4:c.3640G>A

Variant names:

• chr17-43091891-C-T
• rs80356923
• NM_007294.4:c.3640G>A
• BRCA1 p.Glu1214Lys

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-8 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -8 classification points (ACMG Germline Pathogenicity v2019). BP6_Very_Strong

The NM_007294.4(BRCA1):c.3640G>A (p.Glu1214Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000177 (AC=285) in the gnomAD database across 1,614,052 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000209. 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.E1214D: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 91610); p.E1214D: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 496369); p.E1214= (synonymous): Likely_benign (ClinVar VariationId 427302, 3 stars); p.E1214Q: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 917778) 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: 0.00019 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:17
• Conservation: PhyloP100: 4.92
• Publications: 40 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 -8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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 (17/18 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.3640G>A p.Glu1214Lys	missense	Exon 10 of 23	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407581.1		c.3640G>A p.Glu1214Lys	missense	Exon 10 of 24	Prot: NP_001394510.1 UniProt:
	BRCA1 NM_001407582.1		c.3640G>A p.Glu1214Lys	missense	Exon 10 of 24	Prot: NP_001394511.1 UniProt:

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.3640G>Ap.Glu1214Lys

Exon rankExon 10 of 23

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407581.1

HGVSc / HGVSpc.3640G>Ap.Glu1214Lys

Exon rankExon 10 of 24

missense

Prot: NP_001394510.1UniProt: A0A2R8Y7V5

BRCA1 NM_001407582.1

HGVSc / HGVSpc.3640G>Ap.Glu1214Lys

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.3640G>A p.Glu1214Lys	missense	Exon 10 of 23	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.3640G>A p.Glu1214Lys	missense	Exon 10 of 24	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.3640G>A p.Glu1214Lys	missense	Exon 10 of 23	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.3640G>Ap.Glu1214Lys

Exon rankExon 10 of 23

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.3640G>Ap.Glu1214Lys

Exon rankExon 10 of 24

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.3640G>Ap.Glu1214Lys

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: 0.0000591	AC:9	Hom:0	AN:152196	Cov:32
GnomAD2 exomes	AF: 0.0000995	AC:25	Hom:	AN:251288	Cov:
GnomAD4 exome	AF: 0.000189	AC:276	Hom:0	AN:1461856	Cov:33
GnomAD4 genome	AF: 0.0000591	AC:9	Hom:0	AN:152196	Cov:32
TOPMed (Bravo)	AF: 0.0000945	AC:25	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000743	AC:6	Hom:0	AN:80778	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
UK10K	AF: 0.000397	AC:3	Hom:	AN:7562	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00 *	0	9622	0.0000959 *	1	10428
BipEx(Bipolar disorder (including schizoaffective))	0.000176	5	28420	0.000277	8	28844
Epi25(Epilepsy)	0.0000953	4	41958	0.000179	12	66888
SCHEMA(Schizophrenia)	0.0000334	4	119712	0.0000851	16	188038

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
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	1	1	Breast-ovarian cancer, familial, susceptibility to, 1 (2)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
FuncVEP CTI	Benign	0.0067
GPN-Star LLR	N/A	-4.1
GPN-Star score	N/A	4.1
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.55	D
Mutation Taster	N/A	37/63	disease causing
MutationAssessor	Uncertain	2.7	M
PhyloP100	Uncertain	4.9
popEVE	Benign	-4.4
PrimateAI	Benign	0.43	T
PromoterAI	N/A	-0.0053	Neutral
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Varity_R	N/A	0.39
VESM-3B	Benign	-4.4

Showing 29 of 29 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: rs80356923;

hg19: chr17-41243908;

COSMIC: COSV58803882;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar