rs878854958

chr17-43049144-G-Achr17-43049144-G-Cchr17-43049144-G-T

Variant summary

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

The NM_007294.4(BRCA1):c.5383C>T(p.Leu1795Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L1795P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 2.91

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 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 17 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37096584).
• BP6: Variant 17-43049144-G-A is Benign according to our data. Variant chr17-43049144-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240821.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5383C>T	p.Leu1795Phe	missense_variant	21/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5383C>T	p.Leu1795Phe	missense_variant	21/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251438 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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, criteria provided, single submitter	clinical testing	Counsyl	Oct 27, 2017	- -
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

Invitae

Jan 07, 2024

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1795 of the BRCA1 protein (p.Leu1795Phe). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 26287763). This variant is also known as 5242C>T. ClinVar contains an entry for this variant (Variation ID: 240821). 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 with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). 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. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2023

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	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	0.095
Eigen_PC	Benign	0.025
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.75	T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.034	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	-2.3	N;N;.;.;.;.;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.41	T;T;.;.;.;.;T;T
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T
Polyphen		0.91, 0.94	.;P;.;.;.;P;.;.
Vest4		0.37
MVP		0.96
MPC		0.31
ClinPred		0.48	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
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: rs878854958; hg19: chr17-41201161;