17-43057113-T-C

Variant names:

• chr17-43057113-T-C
• rs80357227
• NM_007294.4:c.5216A>G

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.5216A>G​(p.Asp1739Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,786 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000076880: Experimental studies have shown that this missense change affects BRCA1 function (PMID:15004537, 20516115, 23867111, 30209399, 32546644)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1739E) 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: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:2
• Conservation: PhyloP100: 4.74
• Publications: 30 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000076880: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 15004537, 20516115, 23867111, 30209399, 32546644).; SCV001434977: Functional assays showed deleterious effect of this change (PMID: 20516115, 23867111).; SCV000564750: Published functional studies demonstrate a damaging effect: defective protein folding, compromised peptide binding activity and binding specificity, reduced transcriptional activity, impaired cisplatin sensitivity, and classified as non-functional based on a saturation genome editing (SGE) assay measuring cell survival (PMID: 20516115, 23867111, 28781887, 30209399, 30765603, 29884841, 35665744); SCV000591594: Functional studies, including in vitro protein folding, phosphopeptide-binding, and cell-based transcriptional assays, predict this variant to be disease associated and classified as deleterious (Karchin 2007, Mirkovic 2004, Lee 2010, Bouwman 2013, Coyne 2004).; SCV002051822: Functional studies have reported that this variant impacts BRCA1 function in homology-directed repair, transcription activation, human haploid cell proliferation and rescue of Brca1-deficient mouse embryonic stem cells in growth and cisplatin and PARP inhibitor sensitivity assays (PMID: 20516115, 30209399. 32546644).; SCV002645981: This alteration was also found to be deficient in several functional studies including a high-throughput, genome editing, haploid cell survival assay, a yeast small colony assay, binding activity and specificity assays, transcription activation assays and cisplatin sensitivity assays (Findlay GM et al. Nature, 2018 10;562:217-222; Coyne RS et al. Cancer Biol. Ther., 2004 May;3:453-7; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90; Bouwman P et al. Cancer Discov, 2013 Oct;3:1142-55; Woods NT et al. NPJ Genom Med, 2016 Mar;1; Bouwman P et al. Clin Cancer Res, 2020 09;26:4559-4568; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69).
• PM1: In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 80 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 chr17-43057113-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 17-43057113-T-C is Pathogenic according to our data. Variant chr17-43057113-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.5216A>G	p.Asp1739Gly	missense	Exon 19 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5282A>G	p.Asp1761Gly	missense	Exon 20 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5282A>G	p.Asp1761Gly	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.5216A>G	p.Asp1739Gly	missense	Exon 19 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5279A>G	p.Asp1760Gly	missense	Exon 20 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5216A>G	p.Asp1739Gly	missense	Exon 19 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (4)
4	-	-	not provided (4)
2	-	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Breast and/or ovarian cancer (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.7
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.98
MVP		0.87
MPC		0.16
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.84
gMVP		0.82
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: rs80357227; hg19: chr17-41209130;