NM_007294.4:c.5207T>C

Variant names:

• chr17-43057122-A-G
• rs45553935
• NM_007294.4:c.5207T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5207T>C​(p.Val1736Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000591592: Rowling (2010) demonstrated a moderately destabilizing effect on the BRCA1 protein using a biophysical approach, Lee (2010) found a significant effect on protein folding stability using a proteolysis assay, and Mirkovic (2004) and Karchin (2007) predicted a deleterious effect on the protein using in silico models. In addition, two studies showed a strong defect on the transcriptional activity of the variant protein (Carvalho 2007, Lee 2010). The results of other assays and analyses in the literature are somewhat conflicting" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1736D) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:24 U:1
• Conservation: PhyloP100: 5.55
• Publications: 63 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000591592: Rowling (2010) demonstrated a moderately destabilizing effect on the BRCA1 protein using a biophysical approach, Lee (2010) found a significant effect on protein folding stability using a proteolysis assay, and Mirkovic (2004) and Karchin (2007) predicted a deleterious effect on the protein using in silico models. In addition, two studies showed a strong defect on the transcriptional activity of the variant protein (Carvalho 2007, Lee 2010). The results of other assays and analyses in the literature are somewhat conflicting; however these results are limited. One in silico multifactorial-likelihood ratio model classified this as a neutral variant (Easton 2007). One functional study by Rowling (2010) demonstrated that the variant reduced the binding affinity of phosphopeptides; however, another study by Lee (2010) showed intermediate/strong levels of phosphopeptide interaction.; SCV004817576: Functional studies have shown that this variant causes reduced stability and function of the BRCA1 protein (PMID: 17308087, 20378548, 20516115, 23269703). This variant has been reported to be loss-of-function in a haploid cell proliferation assay (PMID: 30209399).; SCV000210207: Published functional studies demonstrate a damaging effect: reduced protein stability, homologous recombination activity, transcriptional activation, and cell survival (Carvalho 2007, Karchin 2007, Lee 2010, Domchek 2013, Findlay 2018, Bouwman 2020); SCV000296377: Functional studies have shown that this variant has a deleterious effect on BRCA1 protein function (PMID: 20516115 (2010), 23269703 (2013), 23867111 (2013), 25748678 (2015), 30209399 (2018), 30765603 (2019), 35196514 (2022)).; SCV000186262: Studies of drug response reported the variant as having "unclear" findings with regard to cisplatin sensitivity, but reported the alteration as deleterious based on Olaparib response and HRR activity (Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55; Bouwman P et al. Clin Cancer Res. 2020 Sep;26(17):4559-4568).; SCV000683271: This variant has been reported to impart an intermediate to a full defect in BRCA1 function in homology-directed DNA repair, transcription activation, PARP inhibitor sensitivity and a haploid cell proliferation assays (PMID: 17305420, 17308087, 20516115, 23269703, 29884841, 30209399, 32546644, 35196514).; SCV000076870: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17308087, 20378548, 20516115, 23269703).; SCV000699213: Multiple independent experimental functional studies reporting this variant have demonstrated: 1.) Reduced localization of BRCA1 fragments containing this variant to double stranded breaks (DSB), 2.) Abolished interaction of BRCA1 fragments bearing this variant with RAP80, a BRCT interacting protein, 3) Moderately impaired homology directed DSB repair, 4.) Altered binding to the BRCT phosphopeptide binding domain, and 5.) Markedly decreased transcriptional activity of the mutant BRCA1 constructs.; SCV000800820: Impaired function on multiple asssays (ref PMID:23269703, Domchek 2013) (PS3_mod).; SCV004847833: In addition, the majority of in vitro functional studies support a loss-of-function impact on protein function (Carvalho 2007, Lee 2010, Rowling 2010, Domchek 2013, Gaboriau 2015, Woods 2016, Findlay 2018).
• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 81 uncertain in NM_007294.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43057122-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 17-43057122-A-G is Pathogenic according to our data. Variant chr17-43057122-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 37648.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.5207T>C	p.Val1736Ala	missense	Exon 19 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5273T>C	p.Val1758Ala	missense	Exon 20 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5273T>C	p.Val1758Ala	missense	Exon 20 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.5207T>C	p.Val1736Ala	missense	Exon 19 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5270T>C	p.Val1757Ala	missense	Exon 20 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5207T>C	p.Val1736Ala	missense	Exon 19 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111908

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000172 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (9)
6	-	-	Hereditary breast ovarian cancer syndrome (6)
5	-	-	not provided (5)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	-	-	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C4554406:Fanconi anemia, complementation group S (1)
1	-	-	Fanconi anemia, complementation group S (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.83
Sift	Benign	0.073	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.80	P
Vest4		0.90
MVP		0.89
MPC		0.12
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.79
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs45553935; hg19: chr17-41209139;