17-43094647-T-C

Position:

• chr17-43094647-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP6

The NM_007294.4(BRCA1):​c.884A>G​(p.Asp295Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,461,868 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (1 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 1.65

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41676542).
• BP6: Variant 17-43094647-T-C is Benign according to our data. Variant chr17-43094647-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 233188.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}. Variant chr17-43094647-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.884A>G	p.Asp295Gly	missense_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.884A>G	p.Asp295Gly	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000796 AC: 20 AN: 251246 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135776

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: 0.000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461868 Hom.: 1 Cov.: 34 AF XY: 0.0000440 AC XY: 32 AN XY: 727228

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: 0.000487

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 31, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 1003A>G; This variant is associated with the following publications: (PMID: 33471991, 34218100, 9582019, 9788437, 9926942, 15343273, 20215511, 26541979, 31954625, 21156238) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 21, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 11, 2020	This missense variant replaces aspartic acid with glycine at codon 295 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual each affected with breast or ovarian cancer, as well as an unaffected control individual (PMID: 21156238, 26541979). This variant has been identified in 20/251246 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. -

Hereditary breast ovarian cancer syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2023	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. This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 295 of the BRCA1 protein (p.Asp295Gly). This variant is present in population databases (rs772684048, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 21156238, 31954625, 34218100). ClinVar contains an entry for this variant (Variation ID: 233188). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 23, 2019

Variant summary: BRCA1 c.884A>G (p.Asp295Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251246 control chromosomes, predominantly at a frequency of 0.00065 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (8e-05 vs 0.001), allowing no conclusion about variant significance. c.884A>G has been reported in the literature in individuals affected with breast and/or ovarian cancer (Manguoglu_2010, Hasmad_2016), but also in a healthy control subject (Manguoglu_2010). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

BRCA1-related cancer predisposition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 29, 2024

This missense variant replaces aspartic acid with glycine at codon 295 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with breast cancer, an individual affected with ovarian cancer and one individual unaffected with cancer (PMID: 21156238, 26541979, 34218100), and this variant also has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_005730). This variant has been identified in 20/251246 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. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 c.884A>G variant was not identified in the literature. The variant was identified in dbSNP (ID: rs772684048) as “With Uncertain Significance allele”, Clinvitae database (as uncertain significance), and the ClinVar database (as uncertain significance, by Ambry Genetics). The variant was not found in the Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database, COSMIC, GeneInsight COGR database, the BIC database, and UMD. This variant was identified in the Exome Aggregation Consortium database (August 8th, 2016) in 8 of 121358 chromosomes (freq. 6.59X10-5) in the following populations: South Asian in 8 of 16504 chromosomes (freq. 0.00048), but was not seen in African, East Asian, Finnish, European (Non-Finnish), and Latino populations, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Asp295 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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 uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;.;.;T;T;.;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.2	M;M;.;.;.;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.2	D;D;D;D;.;D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.023	D;D;D;D;.;D;D;D
Sift4G	Uncertain	0.031	D;D;D;D;.;D;.;D
Polyphen		0.69	P;.;.;B;.;.;.;.
Vest4		0.44
MutPred		0.43		Gain of helix (P = 0.0128);Gain of helix (P = 0.0128);.;Gain of helix (P = 0.0128);.;Gain of helix (P = 0.0128);.;Gain of helix (P = 0.0128);
MVP		0.79
MPC		0.47
ClinPred		0.53	D
GERP RS		1.3
Varity_R		0.36
gMVP		0.24

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: rs772684048; hg19: chr17-41246664;