17-43063928-T-C

Variant names:

• chr17-43063928-T-C
• rs397509227
• NM_007294.4:c.5098A>G

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.5098A>G​(p.Thr1700Ala) 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: "SCV000617448: "Published functional studies demonstrate a damaging effect: defective homology-directed repair activity, transcriptional activation activity, binding activity and specificity, and cell survival (PMID:17308087, 20516115, 21473589, 30209399, 30765603, 35665744)"" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1700K) 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:4 U:1
• Conservation: PhyloP100: 4.92
• Publications: 17 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

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: SCV000617448: "Published functional studies demonstrate a damaging effect: defective homology-directed repair activity, transcriptional activation activity, binding activity and specificity, and cell survival (PMID: 17308087, 20516115, 21473589, 30209399, 30765603, 35665744)"; SCV003933882: Experimental evidence evaluating an impact on protein function have shown that the variant results in loss of function, with the most pronounced variant effect resulting in <10% of normal activity (e.g. Lee_2010, Findlay_2018). PMID: 30209399, 20516115; SCV002645777: One functional study found that the p.T1700A variant did not impact protein folding but it did have a strong effect on the protein function when compared to wildtype. While the p.T1700A variant retained roughly 85% protease sensitivity compared to wildtype, it led to less than 10% binding activity, less than 10% binding specificity, and a loss of around 80% of transcription activity compared to wildtype (Lee MS et al. Cancer Res. 2010 Jun;70:4880-90). Another functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222).; SCV006310891: "Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30209399, 38709234, 35196514)" (PS3 met).
• PM1: In a hotspot region, there are 31 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 67 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 chr17-43063927-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 864948.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837
• PP5: Variant 17-43063928-T-C is Pathogenic according to our data. Variant chr17-43063928-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55399.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.5098A>G	p.Thr1700Ala	missense	Exon 17 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5164A>G	p.Thr1722Ala	missense	Exon 18 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5164A>G	p.Thr1722Ala	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.5098A>G	p.Thr1700Ala	missense	Exon 17 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5161A>G	p.Thr1721Ala	missense	Exon 18 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5098A>G	p.Thr1700Ala	missense	Exon 17 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Hereditary breast ovarian cancer syndrome (2)
1	-	-	BRCA1-related cancer predisposition (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.87	P
Vest4		0.88
MVP		0.96
MPC		0.25
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.86
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.14		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: rs397509227; hg19: chr17-41215945;