17-43063888-A-G

Variant names:

• chr17-43063888-A-G
• rs80357132
• NM_007294.4:c.5138T>C
• BRCA1 p.Val1713Ala

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5138T>C​(p.Val1713Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000076821: Experimental studies have shown that this missense change affects BRCA1 function (PMID:17305420, 17308087, 20516115, 21447777, 30209399)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1713L) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:11 U:4
• Conservation: PhyloP100: 5.76
• Publications: 26 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000076821: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17305420, 17308087, 20516115, 21447777, 30209399).; SCV000916764: "The variant has been reproducibly reported to reduce BRCA1 transactivation activity (Carvalho_2007, Lee_2010, Woods_2016) and phosphopeptide binding /specificity (Lee_2010)." PMID:16267036, PMID:20516115, PMID:14534301, PMID:9159158, PMID:17308087, PMID:7611277, PMID:18992264, PMID:24845084, PMID:25556971, PMID:21309043, PMID:28781887, PMID:30765603, PMID:21447777; SCV006298702: Functional studies indicate this variant impacts protein function [PMID: 20516115, 17308087, 30209399].; SCV000883462: Functional analyses suggest the variant causes altered substrate binding and specificity as well as altered transcriptional activity and impairs homologous repair (Carvalho 2007, Findlay 2018, Lee 2010, Petitalot 2019). PMID: 17308087. PMID: 30209399. PMID: 20516115. PMID: 30257991.; SCV005201800: Published functional studies demonstrate a damaging effect: classified as non-functional based on transcriptional activity, binding activity and specificity, and cell survival (PMID: 17308087, 20516115, 30209399, 30765603, 35665744); SCV001185500: Multiple transcriptional activation functional studies classified this variant as functionally deleterious (Findlay GM et al. Nature, 2018 10;562:217-222; Iversen ES et al. Cancer Epidemiol. Biomarkers Prev., 2011 Jun;20:1078-88; Karchin R et al. PLoS Comput. Biol., 2007 Feb;3:e26; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69; Woods NT et al. NPJ Genom Med, 2016 Mar).
• PM1: In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 63 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43063887-TA-CC is described in ClinVar as Pathogenic. ClinVar VariationId is 1745580.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• PP5: Variant 17-43063888-A-G is Pathogenic according to our data. Variant chr17-43063888-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55412.Status of the report is reviewed_by_expert_panel, 3 stars.

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.5138T>C	p.Val1713Ala	missense	Exon 17 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5204T>C	p.Val1735Ala	missense	Exon 18 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5204T>C	p.Val1735Ala	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.5138T>C	p.Val1713Ala	missense	Exon 17 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5201T>C	p.Val1734Ala	missense	Exon 18 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5138T>C	p.Val1713Ala	missense	Exon 17 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251322 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	1	-	not provided (7)
1	2	-	Breast-ovarian cancer, familial, susceptibility to, 1 (3)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
1	-	-	BRCA1-related cancer predisposition (1)
-	1	-	Fanconi anemia, complementation group S (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.8
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.85
gMVP		0.84
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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: rs80357132;

hg19: chr17-41215905;

COSMIC: COSV58797228;