17-43106487-A-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.181T>G​(p.Cys61Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000187 in 1,604,818 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: "SCV000591246: Functional studies have shown that this variant abolishes ubiquitin ligase activity of the BRCA1-BARD1 heterodimer and impairs BRCA1 DNA repair function, and therefore, it was considered as a pathogenic mutation (Au 2005, Brzovic 2003, Houvras 2000, Millot 2011, Morris 2004, Morris 2006, Ransburgh 2010, Ruffner 2001, Sweet 2010, Caliqo 2009, Humphrey 1997)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C61W) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:67 O:2
• 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

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: SCV000591246: Functional studies have shown that this variant abolishes ubiquitin ligase activity of the BRCA1-BARD1 heterodimer and impairs BRCA1 DNA repair function, and therefore, it was considered as a pathogenic mutation (Au 2005, Brzovic 2003, Houvras 2000, Millot 2011, Morris 2004, Morris 2006, Ransburgh 2010, Ruffner 2001, Sweet 2010, Caliqo 2009, Humphrey 1997).; SCV000839890: Functional in vitro assays showed that this variant was deleterious [PMID 23867111].; SCV002070498: Experimental studies have also demonstrated that this variant disrupts several aspects of BRCA1 function (PMID: 11278247, 9525870, 22172724, 23161852, 23867111).; SCV000075610: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 9525870, 11278247, 22172724, 22843421, 23161852, 23867111).; SCV000271313: "In vitro functional studies have shown that the p.Cys61Gly variant disrupts protein function and produces drug-resistant tumors in mouse models (Brzvoic 1998 and Drost 2011)."; SCV000698888: "several functional studies demonstrated the Cys61Gly mutation affects several functional properties of the BRCA1 NH2-terminal domain (e.g. Brzovic 1998, 2003)."; SCV005848150: Findlay 2018 LOF, Bouwman 2020 Deleterious; SCV007097383: Functional studies demonstrate loss of BRCA1-mediated DNA repair (PMID:26381082;PMID:20103620).; SCV000186957: "In addition, one 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)."; SCV000292141: Functional studies have shown that this variant disrupts BRCA1 function in numerous assays including binding to BARD1, homology-mediated DNA repair, complementation of Brca1-deficient mouse cells to cisplatin and in a haploid cell proliferation assay (PMID: 9525870, 11278247, 11320250, 18243530, 20103620, 23867111, 25823446, 30209399, 32546644).; SCV000210067: Published functional studies demonstrate a damaging effect: variant shown in both mouse and in vitro studies to disrupt proper function of the BRCA1 protein (Ruffner 2001, Chang 2009, Ransburgh 2010, Drost 2011).; SCV000296283: Functional studies report the variant is damaging to proper BRCA1 function (PMIDs: 33087888 (2021), 30209399 (2018), 27272900 (2016), 25823446 (2015), 23867111 (2013), 20103620 (2010), 15569676 (2005), 11320250 (2001).; SCV000602706: BRCA1 protein containing the p.Cys61Gly variant fails to homodimerize (Brzovic 1998), fails to protect the cell from radiation hypersensitivity (Ruffner 2001), and does not mediate homologous recombination repair upon DNA damage (Ransburgh 2010). References: Brzovic P et al. The cancer-predisposing mutation C61G disrupts homodimer formation in the NH2-terminal BRCA1 RING finger domain. J Biol Chem. 1998; 273(14):7795-9. PMID: 9525870. Ruffner H et al. Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci U S A. 2001; 98(9):5134-9. PMID: 11320250. Ransburgh D et al. Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination. Cancer Res. 2010; 70(3):988-95. PMID: 20103620.; SCV000296762: "In addition, experimental studies have shown that this variant disrupts several aspects of BRCA1 function (PMID: 22172724, 23867111)."; SCV004174179: Functional studies have shown a disruptive effect of this alteration on the function of BRCA1 and a resistance to therapy of tumours with this alteration (PMIDs: 22172724, 9525870, 11278247, 18243530).; SCV004823691: Functional in vitro assays showed that this variant increases proteolytic susceptibility of the COOH-terminal portion of the NH2-terminal domain and perturbs the oligomerization properties of BRCA1 (PMID: 9525870), fails to reverse radiation hypersensitivity (PMID: 11320250), and damages ubiquitin ligase activity (PMID: 11278247).
• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43106486-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 54364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-43106487-A-C is Pathogenic according to our data. 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.

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>G	p.Cys61Gly	missense	Exon 4 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.181T>G	p.Cys61Gly	missense	Exon 4 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.181T>G	p.Cys61Gly	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>G	p.Cys61Gly	missense	Exon 4 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.181T>G	p.Cys61Gly	missense	Exon 4 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.181T>G	p.Cys61Gly	missense	Exon 4 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250754 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1452604 Hom.: 0 Cov.: 28 AF XY: 0.0000194 AC XY: 14 AN XY: 723022

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39562

South Asian (SAS) AF: 0.00 AC: 0 AN: 85584

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1104550

Other (OTH) AF: 0.0000167 AC: 1 AN: 60012

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000615874), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000241 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
23	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (24)
19	-	-	not provided (19)
9	-	-	Hereditary breast ovarian cancer syndrome (10)
4	-	-	Familial cancer of breast (4)
4	-	-	Hereditary cancer-predisposing syndrome (4)
2	-	-	Breast carcinoma (2)
1	-	-	BRCA1-related cancer predisposition (1)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Breast neoplasm (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)
1	-	-	Inherited ovarian cancer (without breast cancer) (1)
1	-	-	Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		5.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		0.12	B
Vest4		0.98
MutPred		0.99		Gain of disorder (P = 0.0488)
MVP		1.0
MPC		0.45
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		0.0
SpliceAI score (max)		0.16		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; COSMIC: COSV105897801;