chr17-43106487-A-G

Variant names:

• chr17-43106487-A-G
• rs28897672
• NM_007294.4:c.181T>C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.181T>C​(p.Cys61Arg) 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: "SCV001519582: The most pronounced variant effect in one study reports a loss of E3 ligase activity, BARD1 binding activity and a predicted loss of homology directed repair (HDR) capacity (Starita_2015). PMID:26399788; SCV001574881: Experimental studies have shown that this missense change affects BRCA1 function (PMID:22843421, 25823446, 30209399).; SCV005100938: One functional study found that this nucleotide substitution to have intermediate function in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). Another variant at the same codon, p.C61G (c.181T>G), represents a common mutation in European populations, and has been identified in patients with breast, ovarian, pancreatic, and prostate cancer (Gronwald J et al. J. Med. Genet. 2006 May;43:424-8; Janaviius R. EPMA J. 2010 Sep;1:397-412; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238; Brand R et al. Cancer. 2018 Sep;124:3520-3527; Ibrahim M et al. BMC Cancer. 2018 02;18:179), and has been shown to be deleterious in functional studies (Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Findlay GM et al. Nature. 2018 10;562:217-222).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C61W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 5.10
• Publications: 522 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

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001519582: The most pronounced variant effect in one study reports a loss of E3 ligase activity, BARD1 binding activity and a predicted loss of homology directed repair (HDR) capacity (Starita_2015). PMID:26399788; SCV001574881: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 22843421, 25823446, 30209399).; SCV005100938: One functional study found that this nucleotide substitution to have intermediate function in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). Another variant at the same codon, p.C61G (c.181T>G), represents a common mutation in European populations, and has been identified in patients with breast, ovarian, pancreatic, and prostate cancer (Gronwald J et al. J. Med. Genet. 2006 May;43:424-8; Janaviius R. EPMA J. 2010 Sep;1:397-412; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238; Brand R et al. Cancer. 2018 Sep;124:3520-3527; Ibrahim M et al. BMC Cancer. 2018 02;18:179), and has been shown to be deleterious in functional studies (Towler WI et al. Hum. Mutat. 2013 Mar;34:439-45; Findlay GM et al. Nature. 2018 10;562:217-222).
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 81 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 chr17-43106487-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 17661.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 17-43106487-A-G is Pathogenic according to our data. Variant chr17-43106487-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 54360.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.181T>C	p.Cys61Arg	missense	Exon 4 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.181T>C	p.Cys61Arg	missense	Exon 4 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.181T>C	p.Cys61Arg	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.181T>C	p.Cys61Arg	missense	Exon 4 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.181T>C	p.Cys61Arg	missense	Exon 4 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.181T>C	p.Cys61Arg	missense	Exon 4 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (3)
2	-	-	Hereditary breast ovarian cancer syndrome (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (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	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		5.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.96
MutPred		0.97		Gain of disorder (P = 0.0336)
MVP		1.0
MPC		0.57
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs28897672; hg19: chr17-41258504;