rs80357084

chr17-43106514-G-Achr17-43106514-G-Cchr17-43106514-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4 BP6

The NM_007294.4(BRCA1):c.154C>T(p.Leu52Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000065 in 1,600,984 control chromosomes in the GnomAD database, including 1 homozygotes. 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. L52H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000070 (1 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:7 O:1
• Conservation: PhyloP100: 1.30

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 0 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain in NM_007294.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.35577768).
• BP6: Variant 17-43106514-G-A is Benign according to our data. Variant chr17-43106514-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37421.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=5, Likely_pathogenic=1, Uncertain_significance=6, not_provided=1}. Variant chr17-43106514-G-A is described in Lovd as [Likely_benign]. Variant chr17-43106514-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.154C>T	p.Leu52Phe	missense_variant	4/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.154C>T	p.Leu52Phe	missense_variant	4/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000998 AC: 25 AN: 250602 Hom.: 0 AF XY: 0.0000738 AC XY: 10 AN XY: 135554

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00136

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: 0.0000704 AC: 102 AN: 1448890 Hom.: 1 Cov.: 28 AF XY: 0.0000652 AC XY: 47 AN XY: 721410

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74276

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.000124 AC: 15

Asia WGS AF: 0.000578 AC: 2 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:6 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Uncertain significance, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The p.Leu52Phe variant has been identified in 11 out of 3896 proband chromosomes (frequency 0.003) from individuals with breast and ovarian cancers, and was not identified in 668 control chromosomes (Kim 2006, Han 2006, Sugano 2008 ), increasing the likelihood this variant may have clinical significance. However, it should be noted that this individual was indicated as Asian, and our lab has sequenced the BRCA1 gene in a limited number of individuals from this background such that the full spectrum of benign variation may not yet been defined for this gene in this population and increasing the possibility that this may be a benign variant. It is listed in the dbSNP database as coming from a "clinical source" (ID#: rs80357084) with no frequency information available, and so the frequency of this variant in the general population is not known. The p.Leu52 is conserved in mammals and other species and in-silico or computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that this variant may impact protein function, however this is not predictive enough to assume pathogenicity. Several in vitro studies suggested modest to no effect regarding the role of this variant in centrosome duplication, binding to BARD1, and ubiquitination activity (Brzovic 2003, Morris 2006, Ransburgh 2010, Sarkar 2008, Katoh 2005, Kais 2012, Atipairin 2011). In summary, based on current information presented above, we cannot rule out the possibility that this variant may have clinical significance, but this variant is classified as VUS. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 22, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 11, 2012	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2021	Variant summary: BRCA1 c.154C>T (p.Leu52Phe) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 299432 control chromosomes, predominantly at a frequency of 0.0014 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.154C>T has been reported in the literature predominantly from East Asian cohorts of individuals affected with Breast and/or Ovarian Cancer (example, Sugano_2008, Han_2006, Jang_2012, Kim_2006, Judkins_2005, Eoh_2017, Yoon_2016, Park_2017, Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.5645C>A , p.Ser1882X), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on protein expression, HDR activity, or BARD1 binding (example, Yoon_2017, Starita_2015, Ransburgh_2010, Findlay_2018). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=6). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of any evidence supporting an actionable outcome spanning at-least 12 years of cross sectional review, supported by multiple reports of a neutral functional impact and at-least one co-occurrence as outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 24, 2021	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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2022	Observed in individuals with personal history of breast and/or ovarian cancer, but also in healthy controls (Han 2006, Kim 2006, Sugano 2008, Jang 2012, Hirotsu 2015, Nakamura 2015, Yoon 2017, Hwang 2017, Ryu 2017, Choi 2018, Li 2019, Kim 2020, Momozawa 2021); Published functional studies are conflicting: BARD1 binding, single-stranded DNA repair activity, and cell survival similar to wild-type, mixed results with respect to homology-directed repair and E3 ubiquitin ligase activity, decreased E2 binding, and intermediate increase in centrosome amplification (Brzovic 2003, Morris 2006, Ransburgh 2010, Kais 2012, Towler 2013, Starita 2015, Findlay 2018, Starita 2018, Kweon 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 273C>T; This variant is associated with the following publications: (PMID: 23161852, 17100994, 20967475, 22217648, 26709275, 28111427, 32803532, 21725363, 12732733, 20103620, 19016756, 16949048, 25802882, 27658390, 24249303, 18528753, 25823446, 28392550, 28364669, 21309043, 11573085, 28440963, 25186627, 15385441, 16267036, 29020732, 29215753, 18493658, 28970858, 29176636, 29731985, 30209399, 30415210, 30725392, 31131967, 30866919, 29240602, 31467430, 29752822, 32548945, 31924417, 32973888, 31907386, 32741062, 32377563, 33606355, Paquette[article]2021, 24389207, 20104584, 8944023, 33720123, 32467295, 30287823, 33428613, 33875706, 30219179, 35373174, 16403807) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2022	- -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Breast Center, Key Laboratory of Carcinogenesis and Translational Research	May 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Ovarian cancer Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	1.2	L;L;L;L;.;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;D;N;N;.;N;N;D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0070	D;D;D;D;D;D;D;D;D;.;D;D;D;.
Sift4G	Uncertain	0.025	D;D;D;D;D;D;.;D;D;.;D;D;.;.
Polyphen		1.0, 1.0	.;D;.;.;.;D;.;.;D;.;.;.;.;.
Vest4		0.47
MutPred		0.77		Gain of methylation at K56 (P = 0.0672);Gain of methylation at K56 (P = 0.0672);Gain of methylation at K56 (P = 0.0672);Gain of methylation at K56 (P = 0.0672);.;Gain of methylation at K56 (P = 0.0672);Gain of methylation at K56 (P = 0.0672);.;Gain of methylation at K56 (P = 0.0672);Gain of methylation at K56 (P = 0.0672);Gain of methylation at K56 (P = 0.0672);Gain of methylation at K56 (P = 0.0672);Gain of methylation at K56 (P = 0.0672);.;
MVP		0.99
MPC		0.47
ClinPred		0.22	T
GERP RS		4.6
Varity_R		0.61
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs80357084; hg19: chr17-41258531; COSMIC: COSV58784275; COSMIC: COSV58784275;