chr17-43106478-A-G

Variant names:

• chr17-43106478-A-G
• rs80357064
• NM_007294.4:c.190T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_001407853.1(BRCA1):​c.2T>C​(p.Met1?) variant causes a start lost, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000185680: One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10" and additional evidence is available in ClinVar. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA1 NM_001407853.1 start_lost, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 U:2
• Conservation: PhyloP100: 4.88
• Publications: 97 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000185680: One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). In addition, other functional studies have shown that p.C64R adversely affects the BRCA1/BARD1 complex formation, and leads to increased sensitivity to ionizing radiation and chromosomal instability (Caleca L et al. PLoS ONE, 2014 Feb;9:e86924; Cochran RL et al. Oncotarget, 2015 Sep;6:25240-51).; SCV000688353: Functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, BARD1 binding, ubiquitin E3 ligase, a haploid cell proliferation, sensitivity to ionizing radiation and PARP inhibitors and chromosomal instability assays (PMID: 24516540, 25823446, 26246475, 28398198, 30209399).; SCV001365790: in vitro functional studies support an impact on protein function (Willems 2009, Caleca 2014, Cochran 2015, Findlay 2018).; SCV001582761: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 19287957, 24516540, 25823446).; SCV001469985: Assessment of experimental evidence suggests this variant results in abnormal protein function (PMIDs: 24516540 (2014), 25823446 (2015), 26246475 (2015)).; SCV007107058: PS3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43106478-A-G is Pathogenic according to our data. Variant chr17-43106478-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 54394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407853.1. 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.190T>C	p.Cys64Arg	missense	Exon 4 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.190T>C	p.Cys64Arg	missense	Exon 4 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.190T>C	p.Cys64Arg	missense	Exon 4 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.190T>C	p.Cys64Arg	missense	Exon 4 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.190T>C	p.Cys64Arg	missense	Exon 4 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.190T>C	p.Cys64Arg	missense	Exon 4 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1450124 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 722022

African (AFR) AF: 0.00 AC: 0 AN: 33216

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 85470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5528

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102384

Other (OTH) AF: 0.00 AC: 0 AN: 59940

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (6)
2	-	-	Familial cancer of breast (2)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)
1	-	-	Gastric cancer (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Benign	0.85
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		4.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.99		Gain of disorder (P = 0.0218)
MVP		1.0
MPC		0.50
ClinPred		0.93	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.90
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: rs80357064; hg19: chr17-41258495;