17-43049188-A-G

Position:

• chr17-43049188-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5339T>C​(p.Leu1780Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,760 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1 O:1
• Conservation: PhyloP100: 5.13

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a domain BRCT 2 (size 99) in uniprot entity BRCA1_HUMAN there are 69 pathogenic changes around while only 15 benign (82%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 17-43049188-A-G is Pathogenic according to our data. Variant chr17-43049188-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5339T>C	p.Leu1780Pro	missense_variant	21/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5339T>C	p.Leu1780Pro	missense_variant	21/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251430 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

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: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	research	Cancer Prevention Center, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine	Jun 15, 2016	We observed that 11 HBOC patients with L1780P variant showed typical clinicopathological feature of patients with BRCA1 mutations. When we apply the ACMG standards and guideline for reclassification of L1780P, L1780P is a highly suspected of pathogenic varints of BRCA1. A previous study (Lee et al, 2010) also indicated that L1780P mutation causes adverse effects on cells in functional anlayses. Our re-classification according to the ACMG guidelines for L1780P variant published in Cancer Research and Treatment (Park et al, 2017, e-pub). -
Pathogenic, no assertion criteria provided	case-control	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	May 24, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 20, 2002	- -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Breast Center, Key Laboratory of Carcinogenesis and Translational Research	May 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 08, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 10811118, 20378548, 20516115, 30209399). 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. ClinVar contains an entry for this variant (Variation ID: 55541). This missense change has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 15117986, 17100994, 22217648, 27124784, 27383479, 27488874, 27658390, 28111427, 28288110, 28364669, 29020732, 29770616). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs80357474, gnomAD 0.006%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1780 of the BRCA1 protein (p.Leu1780Pro). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Breast Cancer, National Cancer Center	Jul 05, 2016	A total of 328 breast cancer patients underwent BRCA1/2 genetic screening at the National Cancer Center of Korea. The c.5339T>C variant in the BRCA1 gene was detected in four patients with a family history of breast cancer. It was not detected in 421 healthy controls. We were able to recruit family members of the proband harboring the c.5339T>C variant in the BRCA1 gene. As shown in the pedigree in the published article, two breast cancer patients in this family and the proband were also diagnosed with ovarian cancer 2 years after being diagnosed with breast cancer. The father of the proband also carried the same UV, and his sister died of breast cancer at the age of 46. Another patient who harbored the same variant was diagnosed with breast cancer at the age of 33. Her mother suffered from ovarian cancer and could not participate in this study. The c.5339T>C variant results in an amino acid change from leucine to proline at position 1780. The predicted structure shows that the mutation site is in the middle of a helix in the BRCT domain of BRCA1, forming a hydrophobic patch with its surrounding residues. The BRCT domain is known to recognize and bind phosphorylated pSXXF motifs of FAM175A/Abraxas to recruit BRCA1 to regions of DNA damage. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 02, 2024	Variant summary: BRCA1 c.5339T>C (p.Leu1780Pro) results in a non-conservative amino acid change in 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 8e-06 in 251430 control chromosomes. c.5339T>C has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These data indicate that the variant is very likely to be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and showed damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2020	Published functional studies demonstrate a damaging effect: absent or reduced protease sensitivity, binding activity and specificity, cell survival, and transcription activity (Hayes 2000, Lee 2010, Findlay 2018); Observed in multiple individuals of Korean ancestry with breast and/or ovarian cancer (Choi 2004, Han 2006, Jang 2012, Eoh 2016, Yoon 2016, Ryu 2017); Case control studies in Korean women suggest this variant is associated with hereditary breast and ovarian cancer and may be a pathogenic Korean founder variant (Park 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5458T>C; This variant is associated with the following publications: (PMID: 20378548, 19491284, 15235020, 27124784, 29240602, 27383479, 30415210, 20516115, 15117986, 17100994, 16949048, 22217648, 15172985, 10811118, 28111427, 28781887, 29020732, 28364669, 27658390, 28288110, 27488874, 29770616, 30209399, 30765603, 30309222, 32019279, 30350268) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 02, 2023	The frequency of this variant in the general population, 0.000008 (2/251430 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported as a founder mutation in the Korean population (PMIDs: 28111427 (2017), 28364669 (2017), 30309222 (2019)). It has been found in individuals with breast and/or ovarian cancer (PMIDs: 115117986 (2004), 17100994 (2006), 22217648 (2012), 27124784 (2016), 27488874 (2017), 27658390 (2017), 28364669 (2017), 28111427 (2017), 29020732 (2018), 29240602 (2018), 30309222 (2019), 30350268 (2019), 32019279 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1), and 34645131 (2022)). Additionally, the variant has been reported in healthy individuals (PMIDs: 17100994 (2006), 22217648 (2012), and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA1)). Functional studies describe the variant as having a strong impact on the BRCA1 gene that results in the loss of protein function (PMIDs: 20516115 (2010), 30209399 (2018), 30415210 (2018), 30765603 (2019), 31907386 (2020), 32803532 (2020), 32546644 (2020), and 33087888 (2021)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The p.L1780P variant (also known as c.5339T>C), located in coding exon 20 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5339. The leucine at codon 1780 is replaced by proline, an amino acid with similar properties. This alteration has been detected in many Korean case reports and case-control studies of breast and/or ovarian cancer and is statistically significantly over-represented in the affected populations versus control populations (Choi DH et al. J. Clin. Oncol. 2004 May;22:1638-45; Han SH et al. Clin. Genet. 2006 Dec;70:496-501; Jang JH et al. J. Hum. Genet. 2012 Mar;57:212-5; Yoon KA et al. Cancer Res Treat. 2017 Jul;49:627-634; Eoh KJ et al. Cancer Res Treat. 2018 Jul;50:917-925; Park JS et al. Cancer Res Treat. 2017 Oct;49:1012-1021; Ryu JM et al. Breast. 2017 Jun;33:109-116; Choi MC et al. J Gynecol Oncol. 2018 Jul;29:e43). This variant segregated with disease in two of these studies and is also suggested to be a Korean founder mutation (Ryu JM et al. Breast. 2017 Jun;33:109-116; Park JS et al. Cancer Res Treat. 2017 Oct;49:1012-1021). Analysis of this alteration in yeast, bacterial and mammalian systems show that it is functionally deleterious in terms of cell survival, transcriptional activation, protein binding and protein folding (Findlay GM et al. Nature. 2018 10;562:217-222; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Rowling PJ et al. J. Biol. Chem. 2010 Jun;285:20080-7; Hayes F et al. Cancer Res. 2000 May;60:2411-8). Of note, this alteration is also designated as 5458T>C in some published literature. This amino acid position is highly conserved on sequence alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.41	.;T;.;T;T;T;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D;D;D;T;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.3	.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.0	D;N;.;.;.;.;N;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D;.;.;.;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;D;.;.
Vest4		0.92
MVP		0.96
MPC		0.56
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.92

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: rs80357474; hg19: chr17-41201205;