rs55770810

Variant names:

• chr17-43063931-G-A
• rs55770810
• NM_007294.4:c.5095C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43063931-G-A
• chr17-43063931-G-C
• chr17-43063931-G-T

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.5095C>T​(p.Arg1699Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,828 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: "SCV000076802: Experimental studies have shown that this missense change affects BRCA1 function (PMID:17308087, 17924331, 20516115, 21473589, 21990134, 23867111)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1699G) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:47
• Conservation: PhyloP100: 3.39
• Publications: 157 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: SCV000076802: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 17308087, 17924331, 20516115, 21473589, 21990134, 23867111).; SCV000918722: "At least three publications report experimental evidence evaluating an impact on protein function (Vallon-Christersson_2001, Bouwman_2013, Coquelle_2011) . The most pronounced variant effect results in a drastic reduction in phosphopeptide binding affinity as compared to the wild-type (Coquelle_2011)."; SCV004847834: Multiple in vitro analyses as well as multifactorial probability models are consistent with pathogenicity (Carvalho 2007, Easton 2007, Lee 2010, Coquelle 2011, Spurdle 2012, Bouwman 2013).; SCV006325005: "Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30257991, 32546644, 30765603)"; SCV001434959: Functional assays have shown that this change disrupts BRCA1 binding ability and transcriptional activity (PMID 11157798, 17308087 and 23867111 ). Crystal structure analysis showed that this variant significantly reduce peptide binding through loss of contacts to the main chain of the Phe(+3) residue and a destabilization of the folding BRCT domain (PMID: 21473589).; SCV000186876: Functional studies demonstrated significantly reduced transcriptional binding activity and specificity in human cells with p.R1699W (Vallon-Christersson J et al. Hum. Mol. Genet. 2001 Feb 15;10(4):353-60; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90).; SCV001341520: Functional studies have shown that this variant reduces transcriptional activity (PMID: 11157798, 12496476, 17308087, 22889855) and phosphopeptide binding of the BRCA1 protein (PMID: 21473589) and fails to rescue the lethality phenotype in BRCA1-deficient mouse embryonic stem cells (PMID: 23867111).; SCV000210197: Published functional studies demonstrate a damaging effect: transcription activation, homologous recombination, and protein binding support a deleterious effect (Worley 2002, Coquelle 2011, Nikolopoulos 2007, Bouwman 2013).; SCV000605901: Functional studies found that this variant impaired folding and transcriptional activity (PMIDs: 11157798 (2001), 24845084 (2014), 27272900 (2016)).; SCV000296777: Experimental studies have shown that this missense change disrupts BRCA1 binding ability and transcriptional activity (PMID: 21473589, 20516115, 17308087, 23867111).; SCV001552500: Multiple functional assays assessing transcriptional activation in yeast and mammalian cells have found that the variant is temperature sensitive, reducing transactivation, confirmed by segregation analysis of a large pedigree (Vallon-Christersson 2001, Karchin 2007, Worley 2002 , Thouvenot 2016). The variant falls within the BRCT domain and numerous studies have shown that the variant leads to BRCT folding defect thereby reducing the proteolytic and conformational stability of the domain, evidenced by peptide binding assays and protein 3-dimensional structure (Williams 2004, Glover 2006, Shiozaki 2004, Clapperton 2004, Coquelle 2011, Worley 2002 , Carvalho 2014).; SCV004817595: Functional studies have shown that this variant reduces transcriptional activity (PMID: 11157798, 12496476, 17308087, 22889855) and phosphopeptide binding of the BRCA1 protein (PMID: 21473589) and fails to rescue the lethality phenotype in BRCA1-deficient mouse embryonic stem cells (PMID: 23867111).
• PM1: In a hotspot region, there are 30 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 68 uncertain in NM_007294.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43063930-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37636.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• PP5: Variant 17-43063931-G-A is Pathogenic according to our data. Variant chr17-43063931-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55396.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.5095C>T	p.Arg1699Trp	missense	Exon 17 of 23	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5161C>T	p.Arg1721Trp	missense	Exon 18 of 24	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5161C>T	p.Arg1721Trp	missense	Exon 18 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.5095C>T	p.Arg1699Trp	missense	Exon 17 of 23	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5158C>T	p.Arg1720Trp	missense	Exon 18 of 24	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5095C>T	p.Arg1699Trp	missense	Exon 17 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152068 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251242 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111924

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

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74288

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15256

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000195 Hom.: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
19	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (19)
10	-	-	not provided (10)
6	-	-	Hereditary breast ovarian cancer syndrome (6)
2	-	-	Familial cancer of breast (2)
2	-	-	Fanconi anemia, complementation group S (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	BRCA1-related cancer predisposition (1)
1	-	-	Breast and colorectal cancer (1)
1	-	-	Endometrial carcinoma (1)
1	-	-	Fanconi anemia complementation group A (1)
1	-	-	Malignant tumor of breast (1)
1	-	-	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.97
MPC		0.46
ClinPred		0.96	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.98
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.14		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: rs55770810; hg19: chr17-41215948; COSMIC: COSV107367619;