17-43091794-G-T

Position:

• chr17-43091794-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_007294.4(BRCA1):​c.3737C>A​(p.Thr1246Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 0.0950

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16440833).
• BP6: Variant 17-43091794-G-T is Benign according to our data. Variant chr17-43091794-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240797.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=5, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3737C>A	p.Thr1246Asn	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.3737C>A	p.Thr1246Asn	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 09, 2016	Variant summary: The BRCA1 c.3737C>A (p.Thr1246Asn) variant involves the alteration of a non-conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a "benign" outcome . This variant was not observed in controls (ExAC, 1000 Gs or ESP). A publication cites the variant in two affected individuals that co-occurred with another pathogenic BRCA1 variant, c.4065_4068delTCAA (p.Asn1355fsX10 - classified as pathogenic by LCA). This variant was not, to our knowledge, reported in reputable databases/clinical laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS) - possibly benign." -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2022	Observed in families with breast and/or ovarian cancer who also carried a BRCA1 pathogenic variant (Konecny et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3856C>A, p.Thr1246Asn; This variant is associated with the following publications: (PMID: 27403073, 29884841, 32377563, 21203900) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 22, 2023	In the published literature, this variant has been reported in affected individuals with breast and/or ovarian cancer in the published literature (PMIDs: 21203900 (2011) and 27403073 (2016)). Additionally, the variant has been reported in a study of BRCA1 and BRCA2 regions without essential functions that tolerate variation (PMID: 31911673 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 10, 2024	The p.T1246N variant (also known as c.3737C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 3737. The threonine at codon 1246 is replaced by asparagine, an amino acid with similar properties. This alteration was reported in two of 585 Slovak families with suspected HBOC and was seen in cis with the BRCA1 c.4065_4068del4 mutation in both families (Konecny M et al. Breast Cancer Res. Treat. 2011 Feb;126:119-30). This alteration was also identified in an individual diagnosed with breast cancer (Azim HA et al. Oncol Ther, 2023 Dec;11:445-459). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
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	Aug 17, 2023	This missense variant replaces threonine with asparagine at codon 1246 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two families affected with hereditary breast and ovarian cancer, who also carried a pathogenic variant in the same gene that could explain the observed disease (PMID: 21203900). This variant has not been identified 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-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

Feb 28, 2024

- -

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 p.Thr1246Asn variant was identified in 2 of 1170 proband chromosomes (frequency: 0.002) from Slovak families with hereditary breast or ovarian cancer (Konecny 2011); however, control chromosomes were not evaluated in this study, thus the prevalence of this variant in the general population could not be determined. The variant was detected in association with a pathogenic BRCA1 mutation (c.4065_4068del4) in both of these families, with the authors suggesting that this may be a haplotype (i.e. inherited together on the same chromosome). Of note, the p.Thr1246Asn variant and the c.4065_4068del4 mutation were also found to co-occur in the individual tested by our lab. The variant was not identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, BIC or UMD databases. 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. The p.Thr1246 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out 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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0069	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	4.4
DANN	Benign	0.92
DEOGEN2	Benign	0.16	T;.;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.7	L;L;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.76	N;N;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Benign	0.11	T;D;T;T
Polyphen		0.14	B;.;.;P
Vest4		0.26
MutPred		0.12		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;Loss of sheet (P = 0.0357);
MVP		0.77
MPC		0.35
ClinPred		0.39	T
GERP RS		2.9
Varity_R		0.051
gMVP		0.11

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: rs878854949; hg19: chr17-41243811;