17-43090997-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_007294.4(BRCA1):c.4132G>A(p.Val1378Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,612,732 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1378A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:15
• Conservation: PhyloP100: -0.366

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012888253).
• BP6: Variant 17-43090997-C-T is Benign according to our data. Variant chr17-43090997-C-T is described in ClinVar as [Benign]. Clinvar id is 55111.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43090997-C-T is described in Lovd as [Likely_benign]. Variant chr17-43090997-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4132G>A	p.Val1378Ile	missense_variant	11/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4132G>A	p.Val1378Ile	missense_variant	11/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152132 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000173 AC: 43 AN: 249014 Hom.: 1 AF XY: 0.000201 AC XY: 27 AN XY: 134562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000991

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000662

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000705 AC: 103 AN: 1460600 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 49 AN XY: 726488

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000718

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152132 Hom.: 1 Cov.: 32 AF XY: 0.000498 AC XY: 37 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000554 Hom.: 0

Bravo AF: 0.000487

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.0000595

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:15

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:4

Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Mar 24, 1999	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000026 -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	BRCA1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2020	This variant is associated with the following publications: (PMID: 15385441, 30675319, 23867111, 15235020, 16826315, 24607278, 23982851, 25777348, 16267036, 26689913, 23704879, 32438681) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 08, 2022	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 08, 2019	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 27, 2022	- -

Breast and/or ovarian cancer Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Oct 06, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jun 25, 2014	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 01, 2021

Variant summary: BRCA1 c.4132G>A (p.Val1378Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 249014 control chromosomes, predominantly at a frequency of 0.00099 within the Latino subpopulation in the gnomAD database, including 1 homozygote. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00099 vs 0.001), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. The variant, c.4132G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Judkins_2005, Andres_2014, Machackova_2019, Santonocito_2020, Dorling_2021) but it was also reported in unaffected controls (Dorling_2021). The variant of interest was identified in several sporadic breast cancer cases but it did not segregate with the disease in a large HBOC family (Santos_2014). Co-occurrences with pathogenic variants have been reported (BRCA2 c.2701delC, p.Ala902LeufsX2; BRCA2 c.5763delT, p.Phe1921LeufsX42; BRCA1 c.5335delC, p.Gln1779AsnfsX14; UMD and Internal testing), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated the variant to confer similar activity to wild-type (Bouwman_2013, Lu_2015). Nine ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as benign/likely benign while one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. A recent publication involving the ENIGMA network of collaborators (Parsons_2019) assigned a classification of benign based on likelihood ratios (LRs) for pathogenicity estimated from clinical data of co-segregation with disease, co-occurrence with a pathogenic variant, reported family history, breast tumor pathology and bioinformatic predictions. Based on the evidence outlined above, the variant was classified as benign. -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Val1378Ile variant was identified in 3 of 700 proband chromosomes (frequency: 0.004) from individuals or families with breast or ovarian cancer (Peixoto 2006, El Saghir 2015). The variant was also identified in dbSNP (ID: rs28897690) as "With Uncertain significance allele", ClinVar (classified as benign by Invitae; as likely benign by Ambry Genetics, GeneDx, COGR, Color Genomics and two clinical laboratories; as uncertain significance by BIC), Cosmic (1x in Central nervous system), LOVD 3.0 (8x ), UMD-LSDB (9x as unclassified variant), and in BIC Database (3x with unknown clinical significance). In UMD the variant was identified with a co-occurring pathogenic BRCA2 variants (c.2701delC, p.Ala902LeufsX2) or (c.5763delT, p.Phe1921LeufsX42), increasing the likelihood that the p.Val1378Ile variant does not have clinical significance. The variant was not identified in MutDB, ARUP Laboratories, or Zhejiang University databases. The variant was identified in control databases in 49 of 274850 chromosomes (1 homozygous) at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6406 chromosomes (freq: 0.0002), Latino in 35 of 34190 chromosomes (freq: 0.001), European in 10 of 125746 chromosomes (freq: 0.00008), East Asian in 1 of 18824 chromosomes (freq: 0.00005), and South Asian in 2 of 30406 chromosomes (freq: 0.00007), while the variant was not observed in the African, Ashkenazi Jewish, or Finnish, populations. The p.Val1378 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In addition, this variant was classified by several functional and in silico studies where it was classified once as “likely neutral” (Abkevich 2004), twice as “neutral” (Bouwman 2013, Santos 2014) and once as “unknown” (Judkins 2005). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	0.69
Dann	Benign	0.77
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.68	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.040	N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.50
Sift	Benign	0.27	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T;T;.;.;T;.
Polyphen		0.0010, 0.022, 0.30	.;B;.;.;.;B;.;B;.;.
Vest4		0.20
MVP		0.16
MPC		0.067
ClinPred		0.017	T
GERP RS		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.035

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: rs28897690; hg19: chr17-41243014; COSMIC: COSV58800351; COSMIC: COSV58800351;