chr17-43106516-A-G

Variant names:

• chr17-43106516-A-G
• rs1555597285
• NM_007294.4:c.152T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_007294.4(BRCA1):​c.152T>C​(p.Leu51Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,448,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L51H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.84
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 16 uncertain in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.152T>C	p.Leu51Pro	missense_variant	Exon 4 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.152T>C	p.Leu51Pro	missense_variant	Exon 4 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1448042 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 721070

African (AFR) AF: 0.00 AC: 0 AN: 33164

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100446

Other (OTH) AF: 0.00 AC: 0 AN: 59846

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Leu51Pro variant was not identified in the literature but was identified in ClinVar databases by the Laboratory for Molecular Medicine, as a variant with uncertain significance. The variant was not identified in the in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, UMD, or BIC databases. The p.Leu51 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Pro variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant occurs within the “Zinc finger, RING-type” protein domain and variants in this region have been shown to impact the protein. 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 variant of unknown significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 15, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with proline at codon 51 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has reported that this variant impacts BRCA1 function in a haploid human cell proliferation assay (PMID: 30209399). This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Nov 02, 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 proline, which is neutral and non-polar, at codon 51 of the BRCA1 protein (p.Leu51Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 433685). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;.;.;.;.;D;.;.;T;T;T;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.1	M;M;M;M;.;M;.;.;.;.;.;.;.;.
PhyloP100		4.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;D;N;N;.;N;N;D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;.;D;D;D;.
Sift4G	Benign	0.15	T;D;D;T;D;T;.;D;D;.;D;D;.;.
Polyphen		1.0, 1.0, 1.0	.;D;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.90
MutPred		0.81		Gain of disorder (P = 0.0173);Gain of disorder (P = 0.0173);Gain of disorder (P = 0.0173);Gain of disorder (P = 0.0173);.;Gain of disorder (P = 0.0173);Gain of disorder (P = 0.0173);.;Gain of disorder (P = 0.0173);Gain of disorder (P = 0.0173);Gain of disorder (P = 0.0173);Gain of disorder (P = 0.0173);Gain of disorder (P = 0.0173);.;
MVP		1.0
MPC		0.53
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.93
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555597285; hg19: chr17-41258533;