17-43057077-C-G

Variant names:

• chr17-43057077-C-G
• rs80357442
• NM_007294.4:c.5252G>C
• BRCA1 p.Arg1751Pro

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5252G>C​(p.Arg1751Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: "SCV000668396: In a study using biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with BRCA1 missense variants, this variant was found to have a strong functional effect (Lee MS et al. Cancer Res. 2010 Jun" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1751Q) has been classified as Benign. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 3.17
• Publications: 39 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000668396: In a study using biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with BRCA1 missense variants, this variant was found to have a strong functional effect (Lee MS et al. Cancer Res. 2010 Jun; 70(12):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). This variant was non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet Med. 2019 01;21:71-80).; SCV001575721: Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 15172985, 20516115, 30209399, 30765603).; SCV004227959: Findley 2018: LOF, Woods 2016/Fernandes 2019: func. class 5, Lee 2010: strong functional effect; SCV002048248: "In vitro functional analyses demonstrate defects in transcriptional activity of the BRCA1 protein (Lee 2010). Additionally, a haploid cell survival assay found this variant to be deleterious (Findlay 2018), and a yeast model and fibroblast cell study demonstrated increased cytoplasmic aggregation compared to wildtype (Thouvenot 2016)." PMID: 30765603 PMID: 30209399 PMID: 27802165; SCV006310883: "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 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 76 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 chr17-43057078-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433728.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• PP5: Variant 17-43057077-C-G is Pathogenic according to our data. Variant chr17-43057077-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55482.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.5252G>C	p.Arg1751Pro	missense	Exon 19 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5318G>C	p.Arg1773Pro	missense	Exon 20 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5318G>C	p.Arg1773Pro	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.5252G>C	p.Arg1751Pro	missense	Exon 19 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5315G>C	p.Arg1772Pro	missense	Exon 20 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5252G>C	p.Arg1751Pro	missense	Exon 19 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	2.0	M
PhyloP100		3.2
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.93
gMVP		0.93
Mutation Taster		=24/76	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs80357442;

hg19: chr17-41209094;