NM_007294.4:c.5089T>C

Variant names:

• chr17-43063937-A-G
• rs80356993
• NM_007294.4:c.5089T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PP1_Moderate PP4_Strong PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.5089T>C variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 1697 (p.Cys1697Arg). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.40, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.05 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met). Cosegregation analysis of family(ies) carrying this variant provided evidence towards pathogenicity, and has a Bayes Score of 5.24, within the thresholds for moderate pathogenic evidence (LR >4.3 & ≤18.7) (PP1_Moderate met; internal lab contributor). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 2735.2 (based on Cosegregation LR=730.6; Pathology LR=2.41; Family History LR=1.56), above the thresholds for Very strong evidence towards pathogenicity (LR>350) (PP4_Very strong met; PMID:31131967, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3, PP1_Moderate, PP4_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA003228/MONDO:0011450/092

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 U:2
• Conservation: PhyloP100: 5.76
• Publications: 37 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.5089T>C	p.Cys1697Arg	missense	Exon 17 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5155T>C	p.Cys1719Arg	missense	Exon 18 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5155T>C	p.Cys1719Arg	missense	Exon 18 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.5089T>C	p.Cys1697Arg	missense	Exon 17 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5152T>C	p.Cys1718Arg	missense	Exon 18 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5089T>C	p.Cys1697Arg	missense	Exon 17 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	2	-	Breast-ovarian cancer, familial, susceptibility to, 1 (5)
4	-	-	not provided (4)
1	-	-	BRCA1-related cancer predisposition (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.92	P
Vest4		0.94
MVP		0.99
MPC		0.60
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.95
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80356993; hg19: chr17-41215954; COSMIC: COSV99070787;