17-43071071-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP4

The NM_007294.4(BRCA1):c.4843G>A(p.Ala1615Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1615P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:17 B:1
• Conservation: PhyloP100: 0.0880

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_007294.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.3132732).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4843G>A	p.Ala1615Thr	missense_variant	15/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4843G>A	p.Ala1615Thr	missense_variant	15/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152182 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251402 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135870

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727238

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:17 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:5 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Aug 23, 2002	- -
Benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BS3(Strong)+BP1(Strong)+BP5(Moderate) 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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 31, 2023	This missense variant replaces alanine with threonine at codon 1615 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in transcription activation and mouse Brca1-deficient mouse embryonic stem cells in PARP inhibitors sensitivity and homology-directed DNA repair assays (PMID: 28781887, 29884841, 32546644). This variant has been reported in at least four individuals affected with breast cancer (PMID: 12142080, 22752604, 24884479, 25896959; Color internal data) and in a breast cancer case-control meta-analysis in 4/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002131). This variant has been identified in 1/251402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -

not specified Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 29, 2022	DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.4843G>A, in exon 15 that results in an amino acid change, p.Ala1615Thr. This sequence change has been reported in individuals with personal and/or family history of breast or ovarian cancer (PMID: 12142080, 17453335, 22752604, 24884479, 25896959, 27062684). This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0004 % (dbSNP rs80356987). The p.Ala1615Thr change affects a moderately conserved amino acid residue located in a domain of the BRCA1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala1615Thr substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ala1615Thr change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 21, 2023	Variant summary: BRCA1 c.4843G>A (p.Ala1615Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251402 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4843G>A has been reported in the literature in individuals affected with breast and/or ovarian cancers and/or with a family history of BRCA-related cancers (e.g. Ladopoulou_2002, Juwle_2012, Silva_2014, Dargenio_2015, Azzollini_2016, Bisgin_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2020	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4962G>A; Observed in individuals with personal or family history of breast or ovarian cancer (Ladopoulou 2002, Juwle 2012, Silva 2014, D'Argenio 2015, Azzollini 2016); Published functional studies suggest no damaging effect: transactivation activity similar to wildtype (Woods 2016); This variant is associated with the following publications: (PMID: 22752604, 12142080, 24884479, 25896959, 17453335, 30765603, 28781887, 27062684) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 28, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 06, 2022	The p.A1615T variant (also known as c.4843G>A), located in coding exon 14 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4843. The alanine at codon 1615 is replaced by threonine, an amino acid with similar properties. This variant has been detected in breast and/or ovarian cancer families of Greek, Indian, Brazilian, and Italian ancestry (Ladopoulou A et al. Cancer Lett. 2002 Nov;185(1):61-70; Konstantopoulou I et al. Breast Cancer Res. Treat., 2008 Feb;107:431-41; Juwle A et al. Med. Oncol. 2012 Dec;29(5):3272-81; Silva FC et al. BMC Med. Genet. 2014 May;15:55; D'Argenio V et al. Clin. Chim. Acta. 2015 Jun;446:221-5; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71). One study reports this variant to have functional transcriptional activation (Woods NT et al. NPJ Genom Med . 2016 Mar;1). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 10, 2023	This missense variant replaces alanine with threonine at codon 1615 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in transcription activation and mouse Brca1-deficient mouse embryonic stem cells in PARP inhibitors sensitivity and homology-directed DNA repair assays (PMID: 28781887, 29884841, 32546644). This variant has been reported in at least four individuals affected with breast cancer (PMID: 12142080, 22752604, 24884479, 25896959; Color internal data) and in a breast cancer case-control meta-analysis in 4/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002131). This variant has been identified in 1/251402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 20, 2021

- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

-

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Ala1615Thr variant was identified in the literature in one proband with hereditary breast or ovarian cancer (Ladopoulou 2002). The variant was identified in dbSNP (ID: rs80356987) “With Uncertain significance allele”, the ClinVar database (classified with uncertain significance by Ambry Genetics; classified with uncertain significance by the Sharing Clinical Reports Project, derived from Myriad reports), the BIC database (2X with unknown clinical importance), and UMD (1X as an unclassified variant). The p.Ala1615 residue is conserved in mammals but not conserved in lower organisms and the variant amino acid threonine (Thr) is present in African clawed frog and purple sea urchin, increasing the likelihood that this variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the significance of this variant, although this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1615 of the BRCA1 protein (p.Ala1615Thr). This variant is present in population databases (rs80356987, gnomAD 0.0009%). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 12142080, 17453335, 22752604, 24884479, 25896959, 27062684, 35023674). This variant is also known as 4962G>A. ClinVar contains an entry for this variant (Variation ID: 55302). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 28781887, 30765603, 32546644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.77	T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.3	N;N;.;N;.;N;N;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D;D;.;T;.;D;T;D;D;D
Sift4G	Benign	0.40	T;T;T;T;T;T;T;.;.;T
Polyphen		0.96, 0.61	.;P;.;.;.;.;.;.;P;.
Vest4		0.29
MVP		0.75
MPC		0.083
ClinPred		0.26	T
GERP RS		1.3
Varity_R		0.048
gMVP		0.25

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: rs80356987; hg19: chr17-41223088;