rs80357091

Variant names:

• chr17-43104910-A-C
• rs80357091
• NM_007294.4:c.259T>G

Your query was ambiguous. Multiple possible variants found:

• chr17-43104910-A-C
• chr17-43104910-A-G
• chr17-43104910-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_007294.4(BRCA1):​c.259T>G​(p.Leu87Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,662 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. L87F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.239
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 91 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36205995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.259T>G	p.Leu87Val	missense_variant	Exon 5 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.259T>G	p.Leu87Val	missense_variant	Exon 5 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251246 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000198

Gnomad EAS 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: 0.00000205 AC: 3 AN: 1461662 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111954

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000617 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Dec 27, 2017

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA1 c.259T>G at the cDNA level, p.Leu87Val (L87V) at the protein level, and results in the change of a Leucine to a Valine (TTG>GTG). Using alternate nomenclature, this variant would be defined as BRCA1 378T>G. This variant has been observed in individuals with personal and/or family history of breast and/or ovarian cancer (Shattuck-Eidens 1997, Brzovic 2001). In functional assays, BRCA1 Leu87Val did not inhibit BARD1 protein interaction and was able to rescue homology-directed repair comparable to wild type (Morris 2006, Starita 2015). However, results of the variant's effect on ligase activity varied, with Morris et al. (2006) observing no impact on E3 ubiquitin ligase activity while Starita et al. (2015) showed reduced E3 ligase function compared to wild type. Of note, this variant was not associated with splicing defects or exon skipping (Raponi 2011). BRCA1 Leu87Val was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Leu87Val occurs at a position that is conserved across species and is located in the RING domain and a region known to interact with multiple proteins (Borg 2010, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Leu87Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Jun 08, 2016

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA1 c.259T>G (p.Leu87Val) variant involves the alteration of a non-conserved nucleotide located in the antiparallel alpha-helices flanking the central RING domain thought to be critical for the proper association of the BRCA1 and BARD1 protein (Brzovic_Nat Struct Biol_2001). 2/4 in silico tools predict a benign outcome for this substitution. The variant is absent in 121322 control chromosomes and to our knowledge, it was not reported in affected patients with strong evidence for pathogenicity either at the time of this classification. A functional study demonstrated the variant to retain homology directed repair activity, the BARD1 and UbcH5a binding of BRCA1, however, conflicting evidence has been reported on its effect on the E3 ubiquitin ligase activity (Starita_Genetics_2015 and Morris_HumMolGenet_2006). Due to the lack of clinical information, this variant is classified as variant of uncertain significance. -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2

Feb 19, 2016

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Feb 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 87 of the BRCA1 protein (p.Leu87Val). 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: 16403807, 25823446, 30209399). 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: 54614). This variant is also known as c.378T>G. This missense change has been observed in individual(s) with BRCA1-related conditions (PMID: 9333265). This variant is present in population databases (rs80357091, gnomAD 0.02%). -

Hereditary cancer-predisposing syndrome Benign:1

May 20, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.19
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T;.;.;.;.;.;T;.;T;.;T;T;.;T;T;.;.
Eigen	Benign	0.031
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		0.24
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.31	N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N;N;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.027	D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Benign	0.53	T;D;D;T;D;T;.;.;T;.;D;.;D;.;D;.;.;.
Polyphen		0.30, 0.99, 0.98	.;B;.;.;.;D;.;.;.;.;D;.;.;.;.;.;.;.
Vest4		0.56
MutPred		0.37		Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);.;Gain of methylation at K88 (P = 0.0444);.;Gain of methylation at K88 (P = 0.0444);.;.;Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);.;Gain of methylation at K88 (P = 0.0444);Gain of methylation at K88 (P = 0.0444);.;.;
MVP		0.94
MPC		0.42
ClinPred		0.72	D
GERP RS		1.8
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.38

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

Other links and lift over

dbSNP: rs80357091; hg19: chr17-41256927;