chr17-43045761-A-G

Position:

• chr17-43045761-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5509T>C​(p.Trp1837Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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 (★★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:17 U:1 O:1
• Conservation: PhyloP100: 4.98

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 9) in uniprot entity BRCA1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 17-43045761-A-G is Pathogenic according to our data. Variant chr17-43045761-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 37679.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43045761-A-G is described in Lovd as [Likely_pathogenic]. Variant chr17-43045761-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5509T>C	p.Trp1837Arg	missense_variant	23/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5509T>C	p.Trp1837Arg	missense_variant	23/23	1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:8 Uncertain:1 Other:1

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.991787 -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 27, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Nov 17, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Endocrinology Laboratory, Christian Medical College	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 07, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	PS3(Strong)+PM2(Supporting)+PP4(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 04, 2020	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein Two other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Inconclusive segregation with disease. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2023	Observed in several individuals with a personal or family history of BRCA1-related cancers (PMID: 8968102, 11802209, 15689452, 27741520, 30103829, 29791287, 30254663); Published functional studies demonstrate a damaging effect: decreased transactivation activity, destabilized BRCA1 protein, and decreased cell survival (PMID: 14534301, 15689452, 20516115, 20378548, 30209399, 35665744); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5628T>C; This variant is associated with the following publications: (PMID: 14534301, 30103829, 17305420, 21447777, 16969499, 15235020, 8968102, 23867111, 15689452, 20516115, 15172985, 28781887, 30209399, 30415210, 28111427, 20378548, 18036263, 17005433, 16786532, 16528612, 15609993, 11802209, 29791287, 27741520, 30254663, 28263838, 28324225, 29907814, 29470806, 30765603, 30736435, 34597585, 32719484, 34645131, 32546644, 31907386, 31131967, 33087888, 35459234, 35665744, 25348405) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	BRCA1: PS1, PM2, PM5, PS3:Moderate, PS4:Moderate, BP1 -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2023	The p.W1837R variant (also known as c.5509T>C), located in coding exon 22 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5509. The tryptophan at codon 1837 is replaced by arginine, an amino acid with dissimilar properties. This variant has been seen in multiple ethnically diverse hereditary breast and ovarian cancer (HBOC) syndrome families (Montagna M et al. Cancer Res. 1996;56:5466-9; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Zuntini R et al. Front Genet. 2018 Sep;9:378). In one study, p.W1837R was predicted to be a high-risk variant based on decreased transcription levels, segregation, protease sensitivity, and structural analyses. However, pedigree association analysis suggested that this alteration was not causative, and therefore the authors classified this as a VUS due to the conflicting information (Phelan CM et al. J. Med. Genet. 2005;42:138-46). The p.W1837R variant was also predicted to be likely pathogenic based on functional studies showing 3% structural stability, less than 10% protease sensitivity, roughly 20% binding activity, less than 20% binding specificity, and less than 20% transcription activity (Lee MS et al. Cancer Res. 2010;70:4880-90). 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(7726):217-222). This alteration has been predicted to be deleterious in several other functional and computational studies as well (Williams RS et al. J. Biol. Chem. 2003; 278:53007-16; Abkevich V et al. J. Med. Genet. 2004;41:492-507; Karchin R et al. PLoS Comput. Biol. 2007;3:e26; Bouwman P et al. Cancer Discov. 2013 Oct;3(10):1142-55; Gaiser OJ et al. Biochemistry. 2004 Dec;43:15983-95; Mirkovic N et al. Cancer Res. 2004 Jun;64:3790-7; Woods NT et al. NPJ Genom Med. 2016 Mar). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 08, 2023	This missense variant replaces tryptophan with arginine at codon 1837 of the BRCA1 protein. Computational models consistently predict deleterious impact of this variant on protein structure and function (PMID: 15172985, 15235020, 15609993, 17305420, 27666373). Functional studies have shown that this variant alters protease sensitivity, structural stability, substrate binding, transcriptional activation, a DNA repair pathway, and sensitivity to chemotherapies (PMID: 14534301, 15689452, 16969499, 17305420, 20378548, 20516115, 21447777, 23867111, 28781887, 30209399, 30765603, 32546644). This variant has been reported in individuals affected with early-onset breast cancer, ovarian cancer, and prostate cancer (PMID: 8968102, 11802209, 15689452, 27741520, 28111427, 28263838, 28324225, 29907814, 29907814, 30103829, 30254663). In three families, the variant was identified in an affected parent and their affected child (PMID: 8968102, 15689452, 30254663). Several probability-based multifactorial likelihood models classify the variant as Pathogenic (PMID: 30415210, 31131967, 32546644). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2024	Variant summary: BRCA1 c.5509T>C (p.Trp1837Arg) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Multiple functional studies from different model systems showed mutant protein with decreased stability and solubility, compromised substrate binding activity, increased protease sensitivity, decreased transcription activation level, non-functional HDR pathway and increased cisplatin sensitivity (Phelan_2005, Bouwman_2013, Williams_2003, Lee_ 2010, and Rowling _2010, Findlay_2018), suggesting a defective function of the protein associated with this variant. Structural 3-D modeling study and comparative sequence alignment studies predicted the variant to be cancer-associated or likely to be deleterious (Mirkovic_2004 and Abkevich _2004, respectively). The variant was absent in 247618 control chromosomes (gnomAD). This variant has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Montagna _1996, Meisel_2017, Fernandes_2016, Zanella_2017, Azzollini_2016, Park_2017, Phelan_2005, Zuntini_2018). In one report, the variant was shown to segregate with disease in two affected family members (Zutini_2018). However, in one family the variant was identified in a father with prostate cancer and in his daughter who had breast cancer at age 39 but it was absent in two cousins of the proband affected with breast and bladder cancer (Phelan_2005), which may suggest lack of co-segregation of the variant with the disease or another pathogenic variant may present in this family. The following publications have been ascertained in the context of this evaluation (PMID: 15235020, 27062684, 23867111, 17005433, 27741520, 30209399, 21447777, 17305420, 20516115, 11802209, 28324225, 15172985, 8968102, 28111427, 15689452, 20378548, 14534301, 28781887, 28263838, 30254663). ClinVar contains an entry for this variant (Variation ID: 37679). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1837 of the BRCA1 protein (p.Trp1837Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8968102, 11802209, 15689452, 27741520, 28324225; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37679). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 14534301, 15689452, 17305420, 20516115, 23867111, 30209399). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;T;.;T;T;T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-11	D;D;.;.;.;.;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;D;.;.
Vest4		0.93
MVP		1.0
MPC		0.57
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs80356959; hg19: chr17-41197778;