chr17-43063941-A-T

Position:

• chr17-43063941-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4 BP6

The NM_007294.4(BRCA1):​c.5085T>A​(p.Phe1695Leu) 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. 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. F1695?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 1.51

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 4 ACMG points.

• PM1: In a strand (size 2) in uniprot entity BRCA1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43063941-AAA-AC is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.39142215).
• BP6: Variant 17-43063941-A-T is Benign according to our data. Variant chr17-43063941-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55389.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5085T>A	p.Phe1695Leu	missense_variant	17/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5085T>A	p.Phe1695Leu	missense_variant	17/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251232 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135814

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 Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 22, 1999	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 26, 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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 16528612, 20516115, 30209399, 30257991). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 55389). This missense change has been observed in individual(s) with breast cancer (PMID: 12827452). This variant is present in population databases (rs80357387, gnomAD 0.0009%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1695 of the BRCA1 protein (p.Phe1695Leu). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.13	.;T;.;.;T;T;.;.;.;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.86	D;D;D;T;D;T;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.14	.;N;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.69	N;N;.;N;.;.;N;N;N;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.50	T;T;.;T;.;.;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;.;.;T
Polyphen		0.24, 0.0060, 0.12	.;B;.;.;.;B;.;.;.;B;.
Vest4		0.42
MVP		0.83
MPC		0.26
ClinPred		0.32	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs80357387; hg19: chr17-41215958;