17-43092352-T-G

Position:

• chr17-43092352-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_007294.4(BRCA1):​c.3179A>C​(p.Glu1060Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1060K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 1.94

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 17-43092352-T-G is Benign according to our data. Variant chr17-43092352-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54790.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr17-43092352-T-G is described in Lovd as [Likely_benign]. Variant chr17-43092352-T-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3179A>C	p.Glu1060Ala	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.3179A>C	p.Glu1060Ala	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 17, 2024	The p.E1060A variant (also known as c.3179A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 3179. The glutamic acid at codon 1060 is replaced by alanine, an amino acid with dissimilar properties. This alteration was identified in an individual diagnosed with ovarian cancer (Smith SA et al. Gynecol Oncol, 2001 Dec;83:586-92). This variant has also been reported in Belgian patients with sporadic breast cancer, familial breast and/or ovarian cancer families and hereditary breast cancer families (Claes K et al. Br. J. Cancer. 2004 Mar;90:1244-51). One study classified this alteration as a variant of unknown significance based on in silico models and co-occurrence data, having been identified to co-occur in cis with a BRCA1 pathogenic mutation (Tavtigian SV et al. J. Med. Genet. 2006 Apr;43:295-305). Another study classified this variant as neutral based on a cisplatin sensitivity assay (Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55). Of note, this alteration is also designated as 3298A>C in published literature. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 05, 2017	- -
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). -

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

Likely benign, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 28, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1060 of the BRCA1 protein (p.Glu1060Ala). 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: 11733976, 15026808, 18703817). ClinVar contains an entry for this variant (Variation ID: 54790). 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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 23867111). 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

BRCA1: PM2, BP1, BP2, BS3:Supporting -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Glu1060Ala variant has been previously reported in the literature in at least 7 individuals chromosomes from individuals with hereditary breast and ovarian cancer and the variant was observed to co-occur with a second pathogenic variant 7 times (5 were the same pathogenic variant: p.Glu1221X) (Claes 2004, Tavtigian 2006). In addition, the residue is not conserved in mammals or lower oraganisms and computational analyses (PolyPhen, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein, but this information is not very predictive of pathogenicity. Further, several publications have looked at conservation as an approach to classifying variants and found the variant to be either non-conservative or of having unknown clinical significance (Burk-Herrick 2006; Judkins 2005).The variant has been reported in dbSNP with limited frequency information (rs80357184); it was also reported in 1/8597 individuals from the exome variant server. In summary, based on the above information, the clinical significance of this variant could not be determined with certainty, although we would lean towards a more benign role for this variant. This variant is predicted benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.8	M;M;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-4.3	D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.44
MVP		0.92
MPC		0.47
ClinPred		0.97	D
GERP RS		1.4
Varity_R		0.25
gMVP		0.37

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: rs80357184; hg19: chr17-41244369;